Pulmonary adenocarcinoma with multiple intracranial metastases in two cats

Abstract

Case series summary

This case series describes two cases of feline primary pulmonary adenocarcinoma presenting with multiple intracranial metastases. Both cats exhibited acute and severe neurological deterioration characterised by multifocal neurological signs, significant mass effect, herniation and obstructive hydrocephalus identified on MRI. Histopathological analysis confirmed pulmonary adenocarcinoma with extensive intracranial metastatic disease, a rare and poorly documented phenomenon in cats.

Relevance and novel information

Intracranial metastatic disease from pulmonary adenocarcinoma is rare in cats, and detailed descriptions of MRI characteristics of multifocal cerebral metastases are scarce. This report provides novel insights by documenting the MRI appearance of numerous ring-enhancing intracranial lesions, severe perilesional oedema, mass effect and obstructive hydrocephalus secondary to pulmonary adenocarcinoma metastasis in two cats. Such findings highlight the aggressive clinical course and emphasise the importance of including metastatic pulmonary adenocarcinoma in the differential diagnoses for cats presenting with multifocal intracranial lesions, even in the absence of obvious respiratory signs.

Introduction

Primary pulmonary neoplasms are rare in cats but are associated with a poor prognosis and a high metastatic rate, with dissemination reported in up to 76% of cases and significantly reduced survival in affected individuals.^{1 –3} Diagnosis is usually challenging because of non-specific clinical signs. Intracranial neoplasia occurs in 0.04–2.2% of the feline population, with metastatic involvement reported in approximately 0.6% of cases.^4,5 Here, we describe two cases of primary pulmon-ary adenocarcinomas with multiple intracranial metastases presenting with acute and severe neurological signs.

Case series description

Case 1

An 11-year-old spayed female domestic shorthair cat presented with progressive lethargy, occasional cough and dysorexia. The cat was vaccinated, had no trauma and initially showed mildly increased respiratory sounds. Blood tests were normal, and suspected pneumonia was treated with prednisolone and antibiotics (cefovecin then marbofloxacin), resulting in mild improvement. Behavioural changes developed 3 weeks later, including compulsive right-sided circling and visual impairment.

Upon referral, the cat exhibited reduced mentation, poor response to stimuli and right-sided circling. Physical examination revealed recent weight loss despite a body condition score (BCS) of 4/5, dehydration, mild dermatitis and an upper lip ulcer. Respiratory auscultation and pattern were normal. Neurological examination identified ambulatory tetraparesis with reduced postural reactions in the left thoracic and pelvic limbs. Cranial nerve deficits included absent menace response bilaterally, absent oculovestibular reflex and reduced facial sensation bilaterally. Findings suggested multi-focal lesions affecting the right forebrain and brainstem, with suspected herniation due to increased intracranial pressure (ICP).

Differential diagnoses included neoplasia, infectious or inflammatory encephalitis. Repeated blood work revealed dehydration, elevated creatine kinase (CK) and increased alpha-glycoprotein levels. Serology for feline immunodeficiency virus/feline leukaemia virus and coronavirus was negative. The cat was hospitalised and treated with fluid therapy as well as with mannitol for suspected increased ICP, with mild clinical improvement.

Abdominal and thoracic radiographs, taken when changes in behaviour started, showed no pulmonary or abdominal lesions. Low-field (0.4 T) MRI of the brain revealed multiple intracranial nodules with regular ring-enhancing features on post-contrast T1-weighted (T1W) images, with a mildly T1W hypointense, non-fluid-suppressing centre (Figure 1). Lesions varied in size, from 6 to 14 mm, and at least 10 different foci were seen, well-demarcated, intra-axial (right thalamus, left caudate nucleus, left cerebellar hemisphere, cortical grey matter [GM] and midline medulla oblongata) and extra-axial (right cerebellopontine angle). However, given the low-field MRI, differentiating lesions located in the superficial cortical GM from extra-axial lesions was challenging. Severe areas of bilaterally asymmetrical perilesional oedema within the white matter (WM) with mass effect and obstructive hydrocephalus were noted. Subtentorial and foramen magnum herniation was present. The cat did not recover spontaneous respiration after anaesthesia, and euthanasia was elected because of the grave prognosis.

Figure 1

Case 1: MRI of the brain. T1-weighted (T1W) post-contrast enhancement, dorsal section through the inter-thalamic adhesion showing multiple ring-enhancing lesions around a mildly T1W hypointense, non-fluid-suppressing centre. Two of the six intra-axial lesions are seen in the left thalamus (the largest is indicated by an arrow) and right cerebellar hemisphere, while three lesions affecting the right cerebellopontine angle and the left parietal and left frontal lobes are situated either in the superficial cortex or extra-axially. (a) There is mild, diffuse meningeal enhancement. (b) Transverse section of T1W post-contrast enhancement at the level of the thalamus showing two of the intra-axial lesions in the right thalamus and left caudate nucleus (arrows); no clear midline shift. (c) T2-weighted mid-sagittal view showing a hyperintense lesion in the dorsal brainstem with mild, ill-defined, diffuse parenchymal hyperintensity compatible with generalised oedema; secondary subtentorial herniation (arrowhead), caudal cerebellar indentation and transforamen magnum herniation (arrow) marking increased intracranial pressure

Case 2

A 15-year-old castrated male domestic shorthair cat presented for an acute right head tilt, right-sided circling and generalised ataxia. Initial examination at a veterin-ary clinic revealed bilateral ceruminous otitis externa; no treatment was initiated. Two weeks later, the cat acutely deteriorated, becoming recumbent and anorexic, with a poor BCS of 2/5. Clinical examination at referral showed reduced body condition, dehydration and normal respiratory pattern. Neurological examination showed obtundation, non-ambulatory tetraparesis, right head tilt and absent menace response bilaterally. If supported, the cat displayed compulsive behaviour and pacing, leaning towards the right side. Conscious proprioception was absent in all four limbs with intact segmental spinal reflexes. Neuroanatomical localisation suggested multifocal intracranial disease involving the forebrain and brainstem.

Blood work revealed mild increased urea, globulin and CK. Fluid therapy and mannitol, for suspected increased ICP, were administered without improvement.

Low-field (0.4 T) brain MRI revealed severe, diffuse, multifocal pathology affecting both cerebral hemispheres, the cerebellum and the brainstem (Figure 2). The bilaterally asymmetrical changes consisted of numerous focal lesions of varying size, up to 6 mm in diameter. These were round, with thin, regular ring-enhancement in T1W images. The smaller ones were less distinct with small foci of enhancement. The largest lesion was observed in the left side of the rostral brainstem with central T2-weighted/fluid-attenuated inversion recovery hyperintensity. There was severe, diffuse WM hyperintensity, assumed to be secondary vasogenic oedema, causing severe mass effect. Obstructive hydrocephalus caused by subtentorial herniation and foraminal herniation of the vermis, as well as mild cervical syringomyelia, were present. Humane euthanasia under general anaesthesia was elected because of poor prognosis.

Figure 2

Case 2: MRI of the brain. (a) Dorsal section of T1-weighted (T1W) post contrast at the level of the ventral portion of the third ventricle, showing at the left side of the rostral brainstem a large, spherical lesion with thin, regular ring-enhancement and hypointense core (arrow); several smaller, hyperintense foci are also partially included. (b) T1W post-contrast transverse section at the level of the brainstem lesion previously described. (c) T2-weighted transverse section at the level of the geniculate nuclei showing severe, diffuse white matter hyperintensity assumed to be secondary vasogenic oedema; two intra-axial hyperintense lesions in the cranial brainstem are indicated by arrows

Post-mortem and histology findings

Permission for full-body post-mortem examination was granted for both cases, and similar lung and brain pathology was observed in both cats. In case 1, the lungs contained multiple cream to dark red lesions, with a range in diameter of 0.5–2 cm, which were multifocally depressed and extended into the lung parenchyma. These were accompanied by multifocal pleural thickening with fibrin deposits, suggesting a primary or secondary inflammatory process. Case 2 had a notably small, firm, cream to pale pink discoloured left cranial lobe and a focal 1.2 cm diameter area of depressed pleural thickening on the left caudal lobe (Figure 3). In both cases, post-fixation brain examination revealed multiple variably sized, irregularly round lesions with a granular texture, distributed across several brain regions – often at the grey–white cortical interface – most consistent with a metastatic neoplastic process (Figure 4).

Figure 3

Macroscopic picture of the lung in case 2. Diffuse mottling in shades of pink, red and dark red. The left cranial lung lobe is smaller than expected, irregular and diffusely firm with a white to cream colouration and thickened, roughened pleura (circled). Similar pleural thickening is observed multifocally across other lobes, with fibrin deposits and strands. A focal, irregularly round area of pleural thickening and retraction (1.2 cm) is present on the dorsal left caudal lobe (indicated by an arrow). On palpation, multifocal, moderately firm areas were noted, primarily within the left caudal and right lung lobes

Figure 4

Case 1. Transverse section of the fixed brain at the level of the thalamus, corresponding to the MRI findings shown in Figure 1a. Multifocal, moderately well-demarcated, slightly granular, cream to pale tan with multifocal brown mottling are present within the thalamus and overlying cerebral cortex (circled; note: left and right sides are inverted relative to Figure 1b, reflecting differences in standard orientation conventions between histology and MRI)

Histologically, both cases had similar features. The lung showed multifocal, variably sized and shaped, poorly demarcated, unencapsulated, densely cellular areas of neoplastic proliferation, consisting of highly pleomorphic cells, multifocally forming irregular tubulo-papillary structures or solid areas supported by a thin fibrovascular stroma, with multifocal necrosis and haemorrhage (Figure 5). Neoplastic nodules with similar histological features were found in the brain, multifocally effacing the neuroparenchyma and expanding the Virchow–Robin spaces and extending into the leptomeningeal perivascular spaces, accompanied by oedema and degeneration of the WM (Figure 6). The brain masses were consistent with a metastatic adenocarcinoma, most likely of pulmonary origin, given the absence of primary epithelial neoplasia in other organs on comprehensive histopathological evaluation.

Figure 5

Formalin-fixed, paraffin-embedded tissue section of the lung in case 1 (× 40). Pulmonary neoplastic proliferation of highly pleomorphic, columnar to cuboidal cells supported by a thin fibrovascular stroma. Note the marked anisokaryosis and anisocytosis, and mitotic figures (indicated by arrows). Haematoxylin and eosin stain

Figure 6

Formalin-fixed, paraffin-embedded section of the brain in case 2 (× 10). Cerebral metastasis within the neuropil. Neoplastic cells arranged in solid areas (indicated by asterisks) are supported by a fine fibrovascular stroma. Multifocal small necrotic (circled) and haemorrhagic areas (indicated by an arrow) are observed. Haematoxylin and eosin stain

Discussion

This case series describes two instances of feline pul-monary adenocarcinoma with multiple intracranial metastases, a rare but clinically significant condition.

The MRI findings in these cases are particularly noteworthy. Multiple ring-enhancing intracranial lesions, as observed here, are uncommon in cats, and such imaging features have not been previously described. In dogs, metastatic disease is a primary differential for multifocal brain lesions, with carcinomas often presenting as multiple contrast-enhancing, ill-defined masses with variable peritumoural oedema and no intratumoural haemorrhage.^6,7 Crespo et al ⁸ reported a cat with similar lesions in the cerebral and cerebellar parenchyma, with mild ring enhancement, although an unspecified total number of lesions. Histopathological findings in their case suggested a meningeal origin extending into the adjacent parenchyma. In cats, intraparenchymal lesions with ring enhancement and perilesional oedema are typically associated with gliomas. ⁹ Ring enhancement has been reported in 100% of confirmed gliomas in one study ¹⁰ and is commonly observed across glioma subtypes.^11,12 Although ‘drop metastases’ from gliomas disseminating via cerebrospinal fluid have been reported in dogs, ¹³ no mention of multiple gliomas was found in our feline literature review. Rim enhancement has also been described in meningiomas, with multiple intracranial meningiomas previously reported.^10,14

Cerebral toxoplasmosis in humans shares similar MRI features, including ring enhancement and associated oedema. ¹⁵ However, in feline cases of intracranial Toxoplasma gondii granulomas, MRI findings differ.^16,17 Multiple Cryptococcus species granulomas have been described on brain CT in a cat. ¹⁸ Intracranial abscesses can present with similar imaging features, but are usually described as single lesions, often associated with bite wounds. ¹⁹ Lymphoma, commonly part of multicentric disease, can produce various MRI patterns seen in neoplasia and should be considered in the differential diagnosis.^20,21

Feline pulmonary carcinomas and their potential for widespread metastases have been well-documented, often involving peripheral lymph nodes, distal muscles and bones.^1,22 The so-called ‘lung-digit syndrome’ is associated with a poor prognosis. ²³ The disease in cats progresses more rapidly and metastasises more aggressively compared with dogs. ²⁴ Cerebral, cerebellar and brainstem metastases, as observed in our cases, are uncommon and poorly described in the literature. Troxel et al ²⁵ reported intracranial metastatic disease in 9/160 cats with intracranial neoplasia, three of which were pulmonary adenocarcinomas, although the primary tumour’s histological features were not specified. ²⁵ In addition, 12 cats had two or more discrete tumours of the same type, with no clear origin identified. Another study of 61 cats with intracranial neoplasia documented three metastatic cases, one of which was a bronchogenic carcinoma. ²⁶

The histomorphological patterns and subtypes of feline pulmonary carcinomas are highly variable and less documented compared with those in dogs and humans. In case 2, the neoplasm exhibited a papillary to micropapillary pattern and was classified as a bronchioalveolar subtype, while case 1 was a solid subtype with high cellular pleomorphism and occasional tubular formation, based on recent feline pulmonary carcinoma classifications.^27,28 The tumour also showed intrapleural invasion, consistent with intrapleural carcinomatosis, the wide spread of tumour cells in a distant tissue, described in feline pulmonary carcinoma.^22,27

Crespo et al ⁸ described a cat with expansive meningeal carcinomatosis and lung nodules. Histopathology revealed a neoplastic population of epithelial cells invading the neuropil from the meninges, with neoplastic emboli present in vascular lumina. Although no histological analysis of the pulmonary masses was performed, a primary pulmonary carcinoma with intracranial metastases was suspected, resembling the cases described here. Unlike Crespo et al’s ⁸ case, histopathology in our patients did not demonstrate meningeal carcinomatosis; instead, we identified unencapsulated masses affecting both GM and WM. However, MRI revealed similar multiple intraparenchymal lesions, albeit in greater numbers.

Feline pulmonary carcinoma carries a poor prognosis. Despite moderate differentiation, typically associated with longer survival, extensive metastases, a known negative prognostic factor, likely contributed to the poor outcomes seen in both cases.^1,2,24 The short survival times may reflect cats’ resilience before clinical signs emerge or the aggressive disease nature. Both cases exhibited acute neurological deterioration after prior unspecific weight loss or poor BCS. Only case 1 showed early respiratory signs. Both presentations have been described in pul-monary carcinoma, with or without metastatic spread.^1,25 In addition, this presentation aligns with a case of bronchogenic carcinoma metastasis documented by Tomek et al. ²⁶ In case 1, thoracic radiographs did not reveal obvious pulmonary lesions; however, this may reflect the limited sensitivity of radiography, particularly for detecting small or superficial anomalies. Further investigation into the molecular and imaging detection of feline pulmonary carcinoma, and its metastatic behaviour, is essential to improve early diagnosis and enhance clinical management and prognosis.

Conclusions

These cases illustrate the aggressive metastatic potential of feline pulmonary adenocarcinoma and the diagnostic challenges posed by multifocal intracranial lesions. The MRI features described contribute to the limited characterisation of intracranial metastases in cats and highlight the importance of including metastatic neoplasia in the differential diagnosis of acute neurological deterior-ation. In cats presenting with similar MRI features, metastatic disease, most notably pulmonary carcinoma, should be considered. Thoracic imaging particularly may assist in confirming the primary tumour and guiding clinical decisions.