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Keywords:

  • Brain tumor;
  • Hemangiosarcoma;
  • Lymphosarcoma;
  • Pituitary tumor

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnote
  7. References

Background: This study investigates the frequency, location, and clinical findings associated with 177 secondary brain tumors in dogs.

Hypothesis: Secondary intracranial neoplasia is more common than primary intracranial neoplasia in dogs during the time period studied, and hemangiosarcoma (HSA) is the most common secondary intracranial tumor.

Animals: One hundred and seventy-seven client-owned dogs presented to the Matthew J. Ryan Veterinary Hospital between 1986 and 2003.

Methods: Medical records were searched for a diagnosis of intracranial neoplasia in dogs who underwent complete postmortem examination. Of these dogs, those with a diagnosis of primary intracranial neoplasia were excluded.

Results: Of the 177 secondary brain tumors, 51 (29%) were HSAs, 44 (25%) were pituitary tumors, 21 (12%) were lymphosarcomas, and 21 (12%) were metastatic carcinomas. The average age at diagnosis was 9.6 ± 3.0 years. Most tumors were located in the cerebrum, and a mentation change was the most common presenting clinical sign. On postmortem examination, the same tumor that was in the brain was also present in the lung in 84 cases (47%), in the kidney in 62 cases (35%), and in the heart in 55 cases (31%).

Conclusions and Clinical Importance: Secondary intracranial neoplasia in dogs was more common than primary intracranial neoplasia during the time period studied. Many of these dogs had related disease in other body systems that was apparent on diagnostic tests such as thoracic radiography.

Secondary neoplasms of the central nervous system (CNS) are being recognized with increasing frequency in veterinary species, but secondary intracranial neoplasia in the cat remains uncommon.1,2 Sixty-five percent of pathologically confirmed intracranial tumors diagnosed at one veterinary hospital between 1986 and 1990 were secondary brain tumors as compared with 28% of intracranial tumors examined between 1951 and 1986.1 The incidence of secondary brain tumors may be increasing because animals with systemic malignancies are now being treated more aggressively with chemotherapeutic agents that prolong lifespan, allowing more time for intracranial metastasis to occur.1 Alternatively, the incidence of secondary tumors of the brain may have been underrepresented previously because the cranial vault was not routinely examined as a metastatic site.3,4 In dogs, carcinomas account for the majority of reported brain metastases, followed by sarcomas.1,5

Although intracranial neoplasia is well described in the dog, few reports in this species have focused on secondary tumors of the brain. The purpose of this study was to describe the signalment, clinical signs, radiographic findings, and pathological findings in a large group of dogs with secondary intracranial neoplasia. Data were also collected on dogs with primary intracranial neoplasms over the same time period, and the incidence and signalments of dogs with primary and secondary intracranial tumors were compared.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnote
  7. References

The medical record database at the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania was searched for a diagnosis of secondary intracranial neoplasia in dogs who underwent postmortem examination between 1986 and 2003. At our hospital, the brain is routinely removed and serially sectioned during every postmortem examination. Secondary intracranial neoplasia included any neoplasm occurring at a distant primary site with secondary metastasis inside the cranial vault or a neoplasm that affected (either compressed or invaded) the brain by direct extension from adjacent tissue (eg pituitary and nasal tumors). Only grossly visible pituitary tumors were included; microadenomas identified only histologically were excluded. Round cell neoplasms such as lymphosarcoma (LSA) and histiocytic sarcoma (HS) were included if found at extraneural sites on postmortem examination.

Data collected from the medical records included signalment, clinical history, physical examination findings, and results of thoracic radiography. Therapeutic intervention, survival time, and histopathologic findings, including primary tumor location, metastatic tumor sites, and location of the intracranial tumor, were also recorded. The onset of clinical signs was obtained from the clinical history taken on admission to the hospital, and the duration of clinical signs was defined as the time from the onset of clinical signs until postmortem examination. The presence or absence of several clinical signs related to CNS disease was recorded for each reviewed case. These signs included seizures, apparent cervical pain, vestibular dysfunction, circling, apparent blindness, polyuria and polydipsia (PU/PD), anisocoria, and changes in mentation.

Tumor location within the brain was assigned to 1 of 6 neuroanatomical divisions that included the cerebral cortex, diencephalon (thalamus/hypothalamus), midbrain, pons, medulla, and cerebellum. The presence or absence of tumor in the pituitary gland was also noted. The presence of neoplasia unrelated to the secondary intracranial tumor was recorded for each case based on the postmortem examination report. However, benign dermal, gastrointestinal, and reproductive tumors (eg lipomas, leiomyomas) were considered unlikely causes of clinically relevant disease and were omitted from further analysis. Finally, presence in the lung, liver, spleen, kidney, heart, bone, regional or distant lymph nodes, and adrenal glands of the same tumor seen in the brain was recorded.

Categorical variables were described as proportions or percentages, and comparisons among them were performed using χ2 or Fisher's exact test where appropriate. Normally continuous variables were described using mean ± standard deviation (SD), and nonparametric continuous variables were described with median and range. The unpaired t-test or Wilcoxon's rank sum test was used to compare continuous variables between groups as appropriate. For all comparisons, a P-value of <.05 was considered to be significant. All statistical analyses were performed using SAS statistical software.a

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnote
  7. References

Signalment

Breeds included mixed breed (n=47); Golden Retriever (n=29); Labrador Retriever (n=10); German Shepherd Dog (n=9); and Boxer (n=6). Other breeds were less frequently represented. Of the 29 Golden Retrievers included in the study, 18 dogs had hemangiosarcoma (HSA), which accounted for 35% of those dogs with HSA. Compared with the other secondary intracranial tumor types, Golden Retrievers were significantly overrepresented in the HSA group (odds ratio [OR]=5.7 [95% CI=2.3–14.6], P=.0001). Golden Retrievers comprised only 1 of the 44 dogs with pituitary adenomas or carcinomas (2%) and were significantly underrepresented in this group (OR=0.087 [95% CI=0.002–0.568], P=.002). Three Beagle Dogs were included in the study, and all had pituitary adenomas, which accounted for 12% of those dogs with pituitary adenomas. Compared with the other tumor types, Beagles were significantly overrepresented in the pituitary adenoma group (P= .014). Of the 5 Rottweiler Dogs included in the study, 3 had LSA, which accounted for 14% of those dogs with LSA. Compared with the other types of secondary intracranial tumors, Rottweilers were significantly overrepresented in the LSA group (OR=12.8 [95% CI, 1.4–158.6], P= .0125).

The mean age at presentation for all dogs was 9.6 ± 3.0 years (range, 1.5–16.5 years).

Clinical History and Neurological Examination Findings

The most common presenting neurological signs were changes in mentation (n=77), seizures (n=42), PU/PD (n = 33), and vestibular dysfunction (n=25). Other presenting neurological signs were circling (n=18), apparent blindness (n=15), anisocoria (n=14), and apparent cervical pain (n=11). The most common clinical signs by tumor type are presented in Table 1. Five pituitary adenomas were presumed to be incidental findings at postmortem examination, given the absence of consistent clinical signs in the medical record and the presence of other, unrelated intracranial disease. Twenty dogs with HSA had no neurological signs and presented to the hospital with symptoms of systemic disease, such as lethargy, collapse, hyphema, vomiting, and pericardial effusion. Five dogs with LSA also had no neurological signs of disease and presented to the hospital with clinical complaints such as polyarthropathy, anorexia, diarrhea, and dyspnea.

Table 1.   Clinical signs by tumor types in dogs with secondary intracranial neoplasia.
Tumor Type (Number of Cases for Which Clinical Signs Available)Mean Age at Diagnosis (Years)Median Duration of Clinical Signs (Days)SeizureaVestibular SyndromebNeck PaincBlindnessdMentation ChangeePU/PDf
  • a

    Based on descriptions by the owner or referring veterinarian or witnessed during the dog's stay in the hospital.

  • b

    b Defined by one or more of the following clinical signs: head tilt; nystagmus; disequilibrium.

  • c

    c Either described by the owner or elicited on spinal palpation during the neurological examination.

  • d

    d Defined as an absent menace response in one or both eyes with intact cranial nerve 7 function and no obvious cerebellar disease.

  • e

    e Defined by one or more of the following: behavior change; dementia; dullness; or disorientation.

  • f

    Polyuria/polydipsia (PU/PD); defined subjectively based on the clinical history taken at presentation (no quantitation of water consumption or urination performed).

  • g

    g Six dogs with pituitary adenomas had seizures; however, 3 of these dogs had meningiomas of the cerebrum, 1 dog had an invasive nasal tumor, and 1 dog had a glioblastoma. The seizures were attributed to the other intracranial neoplasms in these 5 cases, and the pituitary tumors were thought to be incidental findings on postmortem examination.

Hemangiosarcoma (49)10.1 ± 2.48 (range 1–1,791)8624138
Pituitary adenoma (20)g10.7 ± 2.790 (range 3–780)111198
Pituitary carcinoma (19)9 ± 3.590 (range 2–251)1311138
Lymphoma (20)7.4 ± 2.826 (range 4–609)762454
Metastatic carcinomas (15)9.7 ± 2.924 (range 3–150)5321123
Nasal tumors (11)10.4 ± 1.227 (range 5–510)702281
Histiocytic sarcoma (7)9.8 ± 2.619.5 (range 7–30)032150
Malignant melanomas (5)11.234 (range 7–104200131

The median duration of clinical signs before diagnosis was 21 days (range, 1–1,791 days). The median time from the onset of clinical signs to death was 21 days (range, 1–1,816).

Radiographic Examination

The results of thoracic radiography were available for 107 of 176 dogs (Table 2). Abnormalities were detected in 58 of 107 dogs (54%). Abnormalities detected on thoracic radiography included presumptive metastatic disease (n = 42), pneumonia (n = 9), megaesophagus (n = 2), lymphadenopathy (n = 2), pleural effusion (n = 2), and cardiac disease (n = 1).

Table 2.   Results of thoracic radiographs by tumor types in dogs with secondary intracranial neoplasia.
Tumor TypesNumber of Dogs with Thoracic RadiographsNo Abnormalities DetectedMetastatic DiseasePneumoniaOther
Hemangiosarcoma3943230
Pituitary adenoma161112Effusion—2
Pituitary carcinoma11612Heart failure—1; megaesophagus—1
Lymphosarcoma131110Lymphadenopathy—1
Metastatic carcinoma7320Lymphadenopathy—1
Nasal tumors65010
Histiocytic sarcoma62310
Malignant melanoma32100

Postmortem Examination

Postmortem examination was performed in 177 of 177 dogs. Secondary intracranial neoplasms diagnosed on postmortem included HSA (n=51), pituitary tumors (n = 44), LSA (n=21), metastatic carcinomas (n=20), nasal tumors (n=11), HS (n=8), and malignant melanomas (n=6). Other tumors were represented less frequently (Table 3). Secondary intracranial neoplasms were divided into 2 categories: tumors occurring at a distant primary site with secondary metastasis inside the cranial vault (“systemic tumors,” n=109) and tumors that compressed or invaded the brain or both by direct extension from adjacent tissue (“adjacent tumors,” n=68). Of the pituitary tumors, 24 were pituitary adenomas and 20 were pituitary carcinomas. Comprising the metastatic carcinomas were tumors originating in the mammary gland (n=3), lung (n=3), anal sac (n=2), prostate (n=2), kidney (n=2), thyroid (n=1), and bladder (n=1). Five were anaplastic carcinomas. Of the anaplastic carcinomas, 3 were confined to the brain and surrounding tissue, such as the eye, hard palate, temporal muscle, and calvaria, and 2 involved the lung and abdominal viscera in addition to the brain. A neuroendocrine carcinoma involving the thoracic cavity, brain, and abdominal cavity was also identified. The nasal cavity tumors included nasal carcinomas (n=9), a nasal sarcoma, and a neuroendocrine carcinoma.

Table 3.   Tumor distribution in 177 dogs with secondary intracranial neoplasia.
Tumor TypeNumber of Tumors Represented
Hemangiosarcoma51
Pituitary adenoma or carcinoma44
Lymphosarcoma21
Metastatic carcinoma20
Nasal neoplasia11
Histiocytic sarcoma8
Malignant melanoma6
Peripheral nerve sheath tumor6
Osteosarcoma3
Anaplastic sarcoma, chondrosarcoma, hepatic neuroectodermal tumor, multilobular tumor of bone, myxosarcoma, primitive mesenchymal tumor, splenic sarcoma1

The specific location of the secondary intracranial neoplasm in the brain was recorded in 144 of 177 cases (Table 4). Most of the neoplasms were located in the cerebrum (n = 88), followed by the cerebellum (n=31), and diencephalon (n = 23). Tumor was present in more than 1 location in the brain in 40 of 144 cases (28%). Tumor cells were present in the pituitary gland in 50 cases, including 44 dogs with pituitary adenomas or carcinomas and 6 dogs with other types of secondary intracranial neoplasia. All of the pituitary adenomas and carcinomas extended outside the normal boundary of the sella turcica. Additionally, the tumor had infiltrated the diencephalon in 1 dog with a pituitary adenoma (4%) and in 7 dogs with pituitary carcinomas (35%). In 1 dog with a pituitary carcinoma, the midbrain as well as the diencephalons was invaded, and in another dog with a pituitary carcinoma, the cerebrum was involved in addition to the diencephalon.

Table 4.   Tumor location within the brain in dogs with secondary intracranial neoplasia.
Tumor Types (Number of Cases)CerebrumDiencephalonMidbrain/PonsPituitary GlandMedullaCerebellumMultifocal
  • a

    In 1 case of nasal carcinoma, metastatic tumor was found in the cerebellum; this tumor also invaded the forebrain. Another nasal carcinoma was found only in the midbrain.

Hemangiosarcoma (39)3343001312/36
Pituitary adenoma (24)01024000
Pituitary carcinoma (20)27020002/20
Lymphosarcoma (18)12742478/17
Metastatic carcinoma (15)13132345/14
Nasal tumors (11)a10010011/11
Histiocytic sarcoma (7)5111112/7
Malignant melanoma (5)4201022/5
Peripheral nerve sheath tumors (6)0020400
Osteosarcoma (3)2000000

On postmortem examination, the same tumor that was in the brain was also present in the lung in 84 of 177 (47%) cases, in the kidney in 62 of 177 (35%) cases, and in the heart in 55 of 177 (31%) cases. Less common sites of metastasis included the liver (n=52, 29%), spleen (n=38, 21%), lymph node (n=35, 20%), and bone (n=15, 8%). For the 109 cases of systemic tumors (excluding the adjacent tumors), 83 (76%) had pulmonary metastases identified on postmortem examination. Organ involvement by tumor type is presented in Table 5.

Table 5.   Location of metastases identified on postmortem examination in 177 dogs with secondary intracranial neoplasms.
Tumor Type (Number of Cases)LungLiverKidneyHeartSpleenBoneLymph NodeEyeAdrenal
Hemangiosarcoma (51)503138402863316
Pituitary tumors (44)000000000
Lymphosarcoma (21)61274411043
Metastatic carcinoma (20)165106341226
Nasal tumors (11)220000300
Histiocytic sarcoma (8)614311411
Malignant melanoma (6)302200212

Other neoplasia unrelated to the secondary intracranial tumor occurred in 32 of 177 dogs (18%). At postmortem examination, other neoplasia unrelated to the pituitary tumor was detected in 14 dogs with pituitary adenomas (58%) and in 3 dogs with pituitary carcinomas (15%). Five dogs with pituitary adenomas had other intracranial neoplasms (meningiomas, n=3; glioblastoma, n=1; and nasal tumor, n=1). One dog with a pituitary adenoma had 3 distinct unrelated types of neoplasia found on postmortem examination, including thoracic wall osteosarcoma with lung metastases, hepatic HSA, and thyroid carcinoma. Among dogs with other types of intracranial tumors, unrelated neoplasia was identified at postmortem examination in 3 dogs with LSA (19%; pheochromocytoma, squamous cell carcinoma, meningioma), 3 dogs with nasal tumors (36%; interstitial cell tumor, choroid plexus tumor, pheochromocytoma), 3 dogs with HS (38%; adrenal adenoma, 2; malignant melanoma, 1), 1 dog with malignant melanoma (perianal carcinoma), 1 dog with neuroendocrine carcinoma (urethral carcinoma), 1 dog with a splenic sarcoma (adrenal adenoma), 1 dog with hepatic neuroectodermal tumor (renal carcinoma), and 1 dog with metastatic carcinoma (Sertoli cell tumor). No dog with intracranial HSA had other, unrelated neoplasia identified on postmortem examination.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnote
  7. References

This study addressed the prevalence of secondary intracranial neoplasia in a hospital population of dogs who underwent postmortem examination over a 15-year period. One hundred and seventy-seven secondary brain tumors were identified. Over the same period, 173 primary brain tumors were identified from our hospital using identical inclusion criteria.6 In general, there were many similarities between dogs with primary and secondary intracranial disease, including mean age at presentation (9.4 versus 9.6 years) and median duration of clinical signs before diagnosis (26 versus 21 days).6 The presenting neurological signs were also similar, although seizures were more common in dogs with primary intracranial neoplasia and nonspecific changes in mentation were more common in dogs with secondary intracranial neoplasia.6–8 Although Boxer Dogs appear to be at increased risk for primary brain tumors, they were not commonly represented in this study.6 Golden Retrievers appear to be overrepresented for both primary and secondary intracranial neoplasms, and among secondary intracranial tumors they were significantly more likely to be diagnosed with HSA and less likely to be diagnosed with pituitary adenoma or carcinoma.7,8

Previous reports have indicated that intracranial metastases in companion animals most commonly affect the cerebrum.1,9 In the present study, the most common locations in the brain for secondary intracranial tumors were the cerebral cortex and the cerebellum. CNS metastasis generally occurs by the hematogenous route, and therefore tumors tend to be located in the “watershed” distributions of the intracranial vasculature.1,9,10

It has been reported previously that 80% of animals with secondary intracranial neoplasia, excluding tumors such as nasal adenocarcinomas that invade the brain directly, have pulmonary metastases identified on postmortem examination.1 This finding is similar to the 76% of cases in our study when the same population (systemic tumor group) is considered. In our study, 47% of all dogs included had pulmonary metastases evident on postmortem examination. Thoracic radiography tended to underestimate the frequency of pulmonary metastases when compared with postmortem examination but nonetheless proved to be a useful screening tool, as 39% of the dogs in this study had evidence of metastatic disease on thoracic radiographs.

Advanced imaging and cerebrospinal fluid analysis were performed in several cases, but the small number of results by tumor type precluded meaningful analysis of these data. Analysis of survival time by treatment modality and by tumor type in this study was also limited owing to the high rate of euthanasia soon after presentation to the hospital in many cases. Postmortem examination was an inclusion criterion in this study, which may have decreased the number of dogs who underwent advanced imaging and aggressive medical or surgical treatments. Dogs discharged from the hospital who die at home or undergo euthanasia at their referring veterinary hospital are less likely to be returned for postmortem examination.

HSA comprised the largest group of secondary intracranial neoplasms in this study. In a previous report, 14.2% of dogs with HSA who underwent complete postmortem examination had brain metastases, although signs of intracranial disease were present in only 7.1% of dogs.11 In our study, 20 of the 51 dogs with metastatic HSA in the CNS did not have signs of neurological disease. It has been reported that dogs with more widely disseminated disease and those with pulmonary metastases are at a greater risk for developing brain metastases.11 In our study, 50 of 51 dogs with HSA had pulmonary metastases, and 82% had changes in their thoracic radiographs consistent with metastatic disease. Every dog had involvement of three or more distinct organs by the tumor on postmortem examination. Common clinical signs for dogs with brain metastases of HSA in this study included a mentation change, seizures, and PU/PD. The mechanism of PU/PD is difficult to explain neurologically, given the absence of histopathological evidence of disease of the diencephalon in these dogs.12 Other possible mechanisms for PU/PD in these dogs include liver disease and renal disease.13 Hypovolemia secondary to blood loss could also cause PD.13

Other studies have included pituitary adenomas as primary brain tumors.14 A decision was made to include them in the current study because pituitary tumors cause clinical signs by excessive secretion of a pituitary hormone or by compression or invasion of the diencephalons or both, although the tumor generally arises in the pars distalis and not in neural tissue.15,16 The most common clinical signs for dogs with pituitary tumors in this study were PU/PD and a depressed or obtunded mentation. Nonspecific clinical signs such as lethargy, disorientation, and staggering were common clinical complaints for dogs with both pituitary adenomas and carcinomas, which is similar to previous reports.15–17 Six dogs with pituitary adenomas in our study had seizures, but 3 of these dogs had meningiomas of the cerebrum, 1 dog had an invasive nasal tumor, and 1 had a glioblastoma. The seizures were attributed to the other intracranial neoplasms in these 5 dogs, and the pituitary tumors were thought to be incidental findings on postmortem examination. Vestibular dysfunction, including nystagmus, was observed in 1 dog with a pituitary adenoma and in 3 dogs with pituitary carcinomas in this study. A previous report of dogs with neurological signs associated with large pituitary tumors found a positional, nonsustained rotary nystagmus in 6 of 8 dogs.15 In this report, a suggested mechanism of nystagmus was necrosis and edema of the brain stem secondary to the pituitary tumor, causing disruption of the medial longitudinal fasciculus.15 Another potential mechanism given the lack of obvious necrosis of the brain stem on postmortem histopathological examination of the dogs in this study would be interruption of the thalamic relay nuclei pathways from the vestibular nuclei and cerebellum.18

In the current study, 21 dogs with metastatic LSA were identified, in contrast to 7 dogs from the same hospital during this time period with LSA confined to the CNS.6 The mean age at presentation (7.4 years) was the same for dogs with metastatic LSA and those with primary CNS LSA, and the clinical signs and tumor distribution were similar.6 It has been reported previously that LSA in the CNS develops most commonly as part of a systemic process in dogs.19–21 In a previous report of CNS LSA in the dog, only 1 of 8 dogs described had primary CNS LSA, and the remaining dogs had multicentric LSA.22 The predominant presenting neurological complaints of the dogs in this report with LSA generally agree with previous reports, in which seizures, vestibular dysfunction, and blindness were common clinical signs.19,22,23 However, in this study, PU/PD appeared to be a more common clinical sign than in previous studies, and multiple cranial nerve deficits (eg bilateral mandibular nerve paralysis) occurred less commonly. Two dogs in this study had intravascular LSA in the brain, which has been reported previously in the dog.24–26

Eleven dogs in this study had disease of the nasal cavity that also involved the brain, and a mentation change and seizures were the most common presenting clinical signs. Seven of these dogs did not have obvious signs of nasal disease, which is consistent with the findings of previous reports.27,28

HS, also known as malignant histiocytosis, is a neoplastic disease characterized by visceral infiltration with atypical malignant histiocytic cells.29 The disease has been primarily described in the Bernese Mountain Dog, and involvement of the CNS has been described.30–34 Of the 8 dogs in this study with HS, only 1 was a Bernese Mountain Dog. Three dogs with HS were Golden Retrievers. Primary HS of the brain has been described previously in the dog.6,33 From the same hospital during the study time period, 5 dogs were identified with primary CNS HS.6 Tumor location in dogs with metastatic and primary CNS HS was similar, with the telencephalon affected in all dogs with primary CNS HS and in 5 of 7 dogs with metastatic HS in which the tumor location in the brain was specified.6

In conclusion, secondary intracranial neoplasia in the dog was more common than primary intracranial neoplasia in the time period studied. Many of these dogs with secondary brain tumors were not presented for neurological signs but those who were presented most commonly with a mentation change or seizures. PU/PD was another common clinical complaint. The potential for secondary intracranial disease should be recognized because as advances in veterinary oncology improve survival times of dogs with systemic neoplasia, and as the lifespan of companion animals increases in general, secondary intracranial tumors may become more common.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Footnote
  7. References
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