Malignant Mesothelioma in Urban Dogs

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                      Malignant Mesothelioma in Urban Dogs
                             M. L. Harbison and J. J. Godleski
                                  Vet Pathol 1983 20: 531
                            DOI: 10.1177/030098588302000504

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Vet. Pathol. 20: 53 1-540 ( I 983)




                      Malignant Mesothelioma in Urban Dogs

                                M. L. HARBISON J. J. GODLESKI
                                             and


  Department of Pathology, Harvard Medical School, Angel1 Memorial Animal Hospital,
                    Brigham and Women’s Hospital, Boston, Mass.



   Abstract. Clinical and postmortem materials from six dogs with a diagnosis of malignant
mesothelioma were studied retrospectively. The dogs were urban pets with clinical signs of
malignant effusions. Two mesotheliomas were pleural, one pericardial, and one peritoneal.
Both pleura and pericardium were involved in one dog, and the pleura and peritoneum in
another. On gross examination at necropsy, diffuse granular or velvety plaques covering
mesothelial surfaces were found in all dogs; firm discrete pleural nodules also were present
in two dogs. Neither distant mestastases nor areas of deep lung invasion were found. The
tumors varied histologically, but the most common type was epithelial with a papillary
pattern. Ultrastructurally, the neoplastic cells had prominent surface microvilli, numerous
desmosomes, and tonofilaments.
   Lung tissue from these dogs and from control dogs was evaluated for the presence of
ferruginous bodies. Asbestos bodies were found in three of five dogs with mesotheliomas but
rarely were found in control dogs. As a group, the mesothelioma cases had significantly
more asbestos bodies and total ferruginous bodies than controls. The clinical and morpho-
logic appearance of canine mesothelioma is similar to human mesothelioma and also may
be associated with exposure to airborne fibers.


   Malignant mesothelioma is a rare spontaneous tumor in dogs. Individual cases
of this neoplasm occumng spontaneously in adult dogs have been reported [3 , 1 1,
12, 14, 15, 181. Although the clinical and pathological features of the tumor have
been examined, associated etiologic or epidemiologic factors have not been de-
scribed. Experimentally, malignant mesotheliomas have been induced in dogs
exposed to intratracheal instillation of crocidolite asbestos and cigarette smoke
[ 131.
   In man, the association between malignant mesothelioma and asbestos exposure
has been well established [2]. Many patients with mesothelioma have had direct
occupational exposure, but the tumor also has been found in family members of
asbestos workers and in people living in the vicinity of an asbestos mine or factory
121.
   Ferruginous bodies-fibers coated with ferritin and amorphous protein-are
found in human lungs and are markers of asbestos exposure [4, 171. The majority
of ferruginous bodies, termed “typical” ferruginous bodies, have cores of amphibole
                                                           53 1



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532                                       Harbison and Godleski

                               Table I. Doas with mesothelioma

  Dog             Breed                Age             Sex          Clinical presentation     Duration
 number                               (years)
    1       Doberman                       8            F       Emaciation, pleural and     1 month
                                                                  peritoneal effusions
      2     Cocker spaniel                 9            M       Decreased exercise tol-     Not stated
                                                                  erance, cough, peri-
                                                                  cardial effusion
      3     Dachshund                     15            F       Anorexia, weakness,         10 days
                                                                  pleural effusions
      4     English setter                I1            M       Polypnea, pleural effu-     1 month
                                                                  sion
      5     Terrier-cross                 10            F       Peritoneal effusion         2 months
      6     Collie-cross                   7            M       Weight loss, anorexia,      1 month
                                                                  pleural and perito-
                                                                  neal effusions*
  * Sixteen months earlier, this dog had benign pericardial and pleural effusions; a pencar-
dotomy was done.

asbestos [9]. These asbestos bodies can be found in the lungs of the general urban
population [9, 161, but the number of asbestos bodiei per gram lung separates
occupational from environmental exposure to asbestos [7, 91.
   We studied clinical and pathologic findings from a series of cases of canine
mesotheliomas. We also examined lung tissue from these dogs and from a group
of control dogs for the presence of fermginous bodies to evaluate the role of asbestos
in this canine neoplasm.

                                     Materials and Methods
   Records of the Pathology Department of Angel1 Memorial Animal Hospital from 1960
to 1980 were reviewed. Six cases, having the coded (Standard Nomenclature of Disease and
Operation-AMA) diagnosis of mesothelioma, were retrieved. Clinical and postmortem
materials from these dogs were available for study. The dogs were urban pets referred to the
hospital. These cases of mesothelioma represented 0.2% of dogs necropsied during this
period.
   All necropsy material had been fixed in 10% neutral buffered formalin. Parafin-embedded
tissues stained with hematoxylin and eosin (HE) were examined by light microscopy. For
histochemical studies, tumor tissue also was stained with periodic acid-Schiff (PAS) with
and without diastase, mucicarmine, and Alcian blue (pH 2.5).
   For electron microscopy, formalin-fixed tumor or tumor tissue removed from parafin
blocks was post-fixed with 2.5% glutaraldehyde and then 1.0% osmium, dehydrated,
embedded in epon, and stained with uranyl acetate and lead citrate.
   The ferruginous body content of lung tissue from five dogs with mesotheliomas was
investigated. Lung tissue also was collected from the next necropsied, age and chronologically
matched dogs and from eight additional control dogs necropsied in 1981. The formalin-
fixed tissue was digested according to a described method [6]. One to five grams of lung
were dissolved in 5 % sodium hypochlorite. After extraction and washing, the resultant
sediment was collected on a 0.45-pm filter (Millipore Co., Bedford, MA) which was cleared




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                                          Table 11. Characteristics of canine mesothelioma
            Tumor pattern                                                                        Distant          Other pathologic
 Dog                                    Location                      Extent                                          findings -
number     (gross/histologic)                                                                   metastasis
  1      Diffuse/well differen-   Bilateral pleura, pen-   Superficial invasion of         No
           tiated                   toneum                   pleural and peritoneal as-
                                                             pects of diaphragm and
                                                             surface of abdominal or-
                                                             gans
  2      Diffuse/poorly differ-   Pericardium              Invasion of myocardium          No                   Severe necrotizing
           entiated                                          and regional lymph nodes                             pericarditis
  3      Diffuse and nodular/     Bilateral pleura         Only parietal pleura in-        No                   Chronic interstitial
           poorly differen-                                  volved                                               nephritis; parathy-
           tiated                                                                                                 roid hyperplasia
  4      Diffuse and nodular/     Bilateral pleura         Extensive parietal pleural      No                   Pleural plaques; in-
           well differentiated                               invasion; superficial inva-                          terstitial cell tu-
                                                             sion of visceral pleura                              mor of testis
                                                             and diaphragm
  5      Diffuse/moderately       Peritoneum               Superficial invasion of sur-    No
           differentiated                                    face of abdominal organs
                                                             and diaphragm
  6      Diffuse/moderately       Bilateral pleura, pen-   Extensive right parietal        Microscopic tumor    Chronic passive
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           differentiated           cardium                  pleural involvement; local     in periadrenal       congestion of liver
                                                             invasion of epicardium,        lymphatics, sinus    and lungs
                                                             esophageal adventitia, re-     of one mesenteric
                                                             gional lymph nodes             lymph node
534                                     Harbison and Godleski




  Fig. 1: Visceral pleural plaques in mesothelioma.

with xylene, mounted on slides, and then examined by light microscopy. Morphologic types
and numbers of ferruginous bodies per gram of wet lung were recorded.


                                                 Results
   The dogs studied and their clinical features are listed in table I. The most
prominent sign in all dogs with mesotheliomas was malignant effusion. The mean
age was 10 f 2.8 years, and there was no sex or breed predilection. In all instances,
the owners eventually elected euthanasia for these dogs after a relatively short,
terminal clinical course, which averaged one month. One dog had a previous
history of benign pleural and pericardial effusions.
   Two neoplasms were pleural, one pericardial, and one peritoneal (table 11). Both
pleura and pericardium were involved in one dog, and the pleura and peritoneum
in another. The tumors were similar in gross appearance with a diffuse pattern
most common. These diffuse lesions were characterized by granular or velvety
plaques covering mesothelial surfaces. Firm discrete nodules, ranging from 0.3 to
4.0 cm in diameter, also were found in two dogs. The mesotheliomas invaded
locally and superficially. The diaphragm was involved in three dogs. Neither distant
metastases nor deep lung invasion was found in any dog. In one instance, neoplastic
cells were identified microscopically in distant lymphatics. No parietal pleural
plaques, similar to those associated with asbestos exposure in man, were described
in these dogs; however, fibrous visceral pleural plaques were present in one dog
(fig. 1). There were few other significant lesions in any of these dogs.
   The tumors varied histologically but were predominantly epithelial. None of the
cases were spindle cell tumors. A histologic spectrum could be seen in individual
tumors as well as from dog to dog. The most common pattern was papillary with
a vascular stroma covered by one or several layers of neoplastic mesothelial cells
(fig. 2). The cuboidal or columnar cells were uniform and had abundant cytoplasm,
distinct borders, and prominent nucleoli. Occasionally the neoplastic cells formed
a less organized proliferation which was associated with a scanty stroma (fig. 3).



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                                        Mesothelioma in Dogs                             535




   Fig. 2: Papillary pattern with vascular stroma covered by uniform, neoplastic mesothelial
cells. HE. Bar = 55 pm.
   Fig. 3: Less organized proliferation of cells with scanty stroma. HE. Bar = 20 pm.
   Fig. 4: Anaplastic cells forming a solid pattern. HE. Bar = 15 pm.
   Fig. 5: Ultrastructural features of malignant mesothelial cells. Bar = 3 pm.




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536                                     Harbison and Godleski




      6a
   Fig. 6: Morphologic types of ferruginous bodies found in digested lung tissue: a. typical
ferruginous body or asbestos body with straight, transparent core; b. atypical fermginous
body with broad core and flared ends; c. atypical segmented and bent ferruginous body. Bar
= 10gm.

Table 111. Ferruginous bodies/gram wet lung in control dogs and dogs with mesotheliomas
                                                            Atypical             Atypical
                                                             broad              segmented      Total
                                         bodies              bodies
                                                                                  bodies       bodies
                                        (fig. 6a)
                                                             (fig. 6b)           (fig. 6c)
 Dog number
      2                                  2                       0                   5            7
      3                                  6                      27                   8           41
      4                                  0                       0                  43           43
    5                                    0                       5                  78           83
    6                                    7                      4
                                                                65                               76
 Mean                                    3.0**                27.6
                                                                19.4                         49.6 f 30.1*
 Matched controls (n = 5)'               0        0            18.1                          18.1 f 15.7
 1981 controls (n = 8)'                < 0.1    < 0.1           5.6                           5.6 f 4.6
 Total controls (n = 13)'              < 0.1**  < 0.1          10.3                          10.4 f 11.6*
  ' Values for controls are mean values.
 * Mean f standard deviations are significantly different (p < .01).
 ** Significantly different (p < .05).

Another epithelial pattern had more anaplastic cells with indistinct borders forming
                      )
a dense mass (fig. 4 .The predominant epithelial pattern of each tumor, in terms
of differentiation, is listed in table 11. Mitotic figures were seen infrequently in the
neoplasms. Four of six mesotheliomas stained positively with Alcian blue. This
staining could be seen at cell borders, in the stroma, and in a few cells with



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                                       Mesothelioma in Dogs                             5 37

vacuolated cytoplasm. One mesothelioma demonstrated light mucicarmine stain-
ing, and two cases stained positively with PAS, but negatively with PAS-diastase.
   The mesotheliomas had prominent ultrastructural features on electron micros-
copy. The neoplastic cells had long slender surface microvilli, numerous desmo-
somes, tonofilaments, and uniform round or oval nuclei (fig. 5). Intracellular
organelles were difficult to evaluate since the material had been fixed initially with
formalin at necropsy and, in two instances, recovered from paraffin blocks.
   Histologic examination of the lungs from these dogs did not reveal interstitial
pulmonary fibrosis or the presence of fermginous bodies.
   Figure 6 illustrates the appearance and table I11 lists the quantity of fermginous
bodies found in digested lung tissue from the dogs in this study. Dogs with
mesothelioma had greater numbers and different morphologic types of ferruginous
bodies compared with controls. Three morphologic types of bodies were found in
the lung samples. The bodies were typically 40 to 70 pm in length. The first type,
typical fermginous bodies or asbestos bodies, was characterized by optically trans-
parent straight cores. These were present in three of five dogs with mesotheliomas
but were a very rare finding in both the age-matched (mean age & 9.8 years) and
the 1981 control dogs. In dogs with mesotheliomas, 2, 6, and 7 bodies/gram wet
weight were found. Most controls had no asbestos bodies. Only three of thirteen
had any bodies, and each of these three dogs had a single asbestos body14 grams of
digested lung tissue.
  Atypical fermginous bodies composed of pale yellow, broad, and regular cores
with flared ends also were found. The majority of fibers with this appearance were
uncoated. These bodies resemble sheet-silicate ferruginous bodies [8]. Three of five
dogs with mesotheliomas had these atypical bodies which also were present very
rarely in control dogs. Two dogs with tumors (dogs 3 and 5 ) had the highest
numbers of both asbestos bodies and these atypical fermginous bodies.
  A third type of ferruginous body was present in the lungs of all dogs, both
controls and dogs with mesotheliomas. These structures were very broad, seg-
mented, and bent fermginous bodies which are thought to contain diatomaceous
earth [ 101. These bodies could be distinguished readily by light microscopy from
asbestos bodies.
  When numbers of ferruginous bodies were compared by the z test for equal
means, the dogs with mesotheliomas had significantlymore total fermginous bodies
than controls (p < .Ol) and more asbestos bodies than controls (p < .05).

                                     Discussion
   Canine malignant mesotheliomas are similar to human mesotheliomas in clinical
and morphologic appearance. People with mesotheliomas usually die from the
complications of their primary lesions [ 11 as did the dogs in this study. The disease
has a rapidly progressive clinical course with a grave prognosis in both species. A
clinical picture highlighted by malignant effusions was present in our dogs and in
other reported cases of canine mesotheliomas [3, 1 1, 12, 14, 15, 181.

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538                                   Harbison and Godleski

   The gross lesions of the neoplasm in man and dog are similar. Tumor growth
occurs primarily by local extension, and distant metastases are not a prominent
feature. Histologically the mesotheliomas in these dogs were predominantly of the
epithelial type and resembled this type in man. The fibrous or spindle cell variety
of mesothelioma, found also in man, was not seen. The histologic appearance of
other reported canine mesotheliomas also has been epithelial [ 3 , 14, 181. Finally,
human and canine mesotheliomas share the same ultrastructural characteristics.
Our electron microscopic findings are similar to those found in a previous case
report of canine mesothelioma [ 181.
   Fibers coated with iron and protein were found in digested lung tissue from all
dogs. As a group, dogs with malignant mesothelioma had significantly more
ferruginous bodies in their lungs than did controls. This quantitative difference
suggests that exposure to airborne fibers was not the same in the two groups of
dogs. Our findings also suggest a qualitative difference in the types of fibers inhaled
by controls and dogs with mesotheliomas. Asbestos bodies were present in three
dogs with tumors but were virtually absent in controls. Similarly, atypical pale
yellow ferruginous bodies were found in three dogs with mesotheliomas.
   Asbestos bodies have been found in the lungs of nearly everyone in the general
population [ 101and the prevalence of lung ferruginous bodies is greater in residents
of urban than rural communities [2]. Asbestos bodies are markers of exposure, and
numbers of bodies in urban patients correlate in a general way with occupation. In
one study, most women and male office workers had less than 50 asbestos bodies
per gram wet lung and were considered to have environmental exposure to asbestos.
On the other hand, many steel and construction workers had greater than 100
bodies per gram and were considered to have additional occupational exposure
[7]. Asbestos workers themselves had many times more bodies (lo5 to lo7 per
gram) [9]. Considering people with the highest exposures, numbers of asbestos
bodies correlate generally with the presence of diffuse interstitial pulmonary fibrosis
[5]. In people with low exposure, however, no correlations between numbers of
bodies and disease have been made [5, 8, 91.
   Dogs in this study had fewer asbestos bodies in their lungs than have been found
in people. Most control dogs had no asbestos bodies, unlike the human findings.
The higher prevalence and the greater numbers of asbestos bodies in dogs with
mesotheliomas may signal a difference in residence or life-style. It also is possible
that a dog could have a bystander exposure as a family pet of an asbestos worker.
   Interestingly, broad segmented atypical ferruginous bodies were present in all
dogs but are observed very infrequently in man [lo]. The significance of these
bodies is not known.
   Our discussion of fibers found in these dogs is based on structures seen by light
microscopy. We assume that morphologically typical ferruginous bodies found in
dogs contain asbestos as they do in people. Whether the numbers of these asbestos
bodies found in the dogs with mesotheliomas reflect exposures to asbestos which



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                                         Mesothelioma in Dogs                             539

have had a carcinogenic effect is not known. In people, the number of asbestos
bodies is considerably less than the total number of asbestos fibers in the lungs [ 5 ] .
Most fibers are uncoated and invisible by light microscopy, but the number of
coated fibers is usually a reliable indication of the total number of fibers. In addition
to total numbers, the type of asbestos fiber and its physical dimensions are
important in asbestos-related human diseases. For example, mesothelioma appears
to be associated with increased numbers of amphibole fibers [ 5 ] . Thus, an analysis
of both coated and uncoated fibers with electron optical techniques is an ideal
means to describe the total retention of inhaled fibers in an animal's lungs.
However, since these specialized techniques are difficult and time consuming and
are not readily available in all centers, counting fibers from lung digests can be a
useful technique to gain preliminary information in previously unstudied areas.

                                        Acknowledgements
  We wish to thank Rebecca Stearns for technical assistance. This work was supported by
Public Health Service Grant 5T32 RR07000 in veterinary and comparative pathology.

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540                                    Harbison and Godleski

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Request reprints from Dr. Margaret Harbison, Department of Physiology, Harvard School
of Public Health, 665 Huntington Avenue, Boston, MA 02 1 15 (USA).




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