Introduction

Hamartomas are developmental lesions due to exaggerated, focal, and disorganized proliferation of tissue elements.¹ Indeed, the term hamartoma refers to the presence of the lesion at birth, with a growth parallel to that of the animal.² Although hamartomas are considered to be histologically benign, these lesions may lead to overt clinical manifestations owing to their space-occupying or compressive nature on adjacent structures and their hemorrhagic tendency.² In animals, hamartomas are described as vascular, bile duct, ovarian interstitial cell, mesenchymal, pulmonary microcystic, muscle, melanotic, collagen types and cutaneous annexes.³ Cerebral hamartomas in humans are usually formed of a mix of mature disordered glial and neuronal cells, often arising in the hypothalamus.⁴ In the canine nervous system, several histological types of hamartoma have been reported, arising from blood vessels, neuronal and glial cells, and peripheral nerve fibers.³ The clinical and histopathological features of a hypothalamic neuronal hamartoma in a dog have been previously described in a single case report more than 40 yr ago.⁵ To the authors’ knowledge, the record of this rare disease presented here is the first with a thorough MRI description and with both clinical and histopathological features.

Case Report

A 1 yr old female vizsla was referred with a history of progressive neurological signs, since her adoption at 3 mo of age. Before presentation, the main complaint was a 4 mo history of 48 hr long episodes of compulsive left circling, absence of interaction with the owner, and sleep deprivation. These episodes occurred every 15 days. A single dose of prednisolone^a (1 mg/kg, subcutaneously) was administered 1 mo before presentation, without clinical improvement. No history of an estrous cycle was reported. Physical examination was unremarkable. On neurological examination a depressed mental status, left head tilt, compulsive pacing, and left circling were observed. Ipsilateral proprioceptive deficits, positional horizontal nystagmus, and left eye positional ventral strabismus were seen. The remaining neurological examination was normal. Based on these clinical findings, a left brainstem lesion was suspected; however, a forebrain lesion (right thalamus) could not be ruled out. Differential diagnoses included congenital, inflammatory, and, less likely, neoplastic diseases.

Complete blood cell count and serum biochemistry were unremarkable. A brain MRI (0.22T MrV; Paramed) under general anesthesia was performed. An ill-defined, intra-axial, space-occupying lesion (1.9 × 1.5 × 1.9 cm) in the ventral middle cranial fossa region was detected. The mass was mildly and heterogeneously hyperintense to gray matter on T2-weighted (T2W; Figure 1A) and isointense to gray matter on precontrast T1-weighted (T1W) images, without enhancement after gadolinium administration on postcontrast T1W images (Figure 1B). The lesion caused a mild compression associated with caudal displacement of the adjacent cranial midbrain. Additionally, a strongly enhanced small area on the right part of the pituitary fossa was seen, consistent with normal pituitary tissue. A cerebrospinal fluid tap was not attempted owing to a suspicion of increased intracranial pressure and risk for caudal transtentorial herniation. Based on imaging findings, our differential diagnosis included neoplasia, congenital malformation, or, less likely, granuloma. The owner elected for euthanasia.

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At postmortem examination, after removal of the brain, the pituitary fossa appeared enlarged and both cavernous sinuses were clearly visible (Figure 2A). A median, rounded, well-defined grayish mass, resembling normal cerebral tissue, covered the ventral surface of the hypothalamus, caudal to the optic chiasm and just cranial to the ventral surface of the mesencephalon (Figure 1C). The pituitary gland was compressed and cranially dislocated (Figure 2B).

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Tissue specimens were fixed in 10% buffered formalin, embedded in paraffin, and stained with hematoxylin and eosin. Histologically, the mass was composed of abnormally distributed normal neurons and glia, with a prevalence of neuronal elements. Luxol fast blue combined with periodic acid–Schiff staining used for a sub-macro histological study confirmed the region was disorganized. Discrete nodular foci of abnormally distributed neurons interspersed with glial cells and a few large ganglion-like balloon cells were present (Figure 3A). Compared with the hypothalamic area of a healthy 12 mo old dog, the glial fibrillar acidic protein–positive glial cells were more abundant and diffusely distributed. Synaptophysin immunoreaction revealed a more crowded network of synapse-associated proteins. Immunohistochemistry for phosphorylated neurofilaments revealed disorganized tracts of axons (Figure 3B). The neuronal population was composed of mature small-to-intermediate neuron-specific enolase–positive neurons.

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Based on histological and immunohistochemical findings, a hypothalamic neuronal hamartoma was diagnosed.

Discussion

Only one case report of neuronal hamartoma in the canine nervous system has been made describing a lesion located in the hypothalamus.⁵ As it was a late-1970s case report, only limited clinical and histopathological details were given, and no advanced diagnostic imaging features were available at that time.⁵ We described the second canine hypothalamic hamartoma case, adding clinical and histopathological details and presenting, for the first time, a thorough MRI description of this rare disease.

In humans, nervous tissue hamartomas are typically located in the ventral hypothalamus and are termed hypothalamic hamartomas (HHs).⁶ The first human HH case report was described by Le Marquand in 1934.⁷ In the following years, two different primary subgroups of HHs and their related clinical phenotypes have been described: (1) pedunculated (parahypothalamic) and (2) sessile (intrahypothalamic).⁶ The pedunculated form is responsible for pituitary axis disorder, specifically central precocious puberty (CPP), whereas sessile HHs are consistently related to epileptic and psychiatric syndromes.⁸ Central precocious puberty is the main feature of the parahypothalamic hamartoma type in humans because of premature activation of the hypothalamic–pituitary–gonadal axis.⁹ Gelastic seizures, characterized by spontaneous mirthless laughter often in isolation, represent the pathognomonic seizure type of sessile HHs, although multiple seizure types will occur over time.¹⁰

Diagnosis of human HHs is accomplished with MRI; these lesions appear as homogeneous, nonenhancing, soft-tissue masses, isointense to gray matter on T1Wand relatively hyperintense on T2W images.¹¹

Main differential diagnoses for sellar and parasellar lesions are plentiful in the adult; however, strictly considering sellar lesions, up to 90% of pituitary lesions are histologically confirmed as adenomas. In children, craniopharyngiomas, chiasmal gliomas, and hypothalamic astrocytoma are the most common sellar lesions.¹²

Imaging features that could differentiate HHs from other sellar and parasellar masses are specific MRI signal features (isointense on T1W and slightly hyperintense on T2W images), lack of contrast medium uptake, and a steady aspect on follow-up imaging.¹¹

Treatment of HH is challenging and complex; in human medicine, there are no controlled or comparative trials for HH management. Of the clinical syndromes related to HHs, epilepsy, particularly gelastic seizures, is typically refractory to medical treatment.¹⁰ Surgical resection is currently recognized as the best treatment for gelastic seizures, even reversing cognitive and behavioral decline.¹⁰ Different surgical approaches have been developed for HH lesions, mainly based on their anatomic features.¹³ Other modalities, less invasive than surgery, have been developed: stereotactic radiofrequency thermocoagulation, stereotactic radiosurgery (Gamma Knife radiosurgery), and vagal nerve stimulation.¹⁴ In contrast, CPP can usually be treated successfully with hormonal therapy.¹⁴

In human studies, specific HH histopathological features consist of abnormally distributed but normal cytological appearance of neurons and glia, with a prevalence of neuronal elements in 58% of cases.⁸ The predominant pattern is nodular. The cellularity of HHs appears to change independently of lesion volume and patient age, but glial cells could be more predominant with increasing age.⁸

The hypothalamus is physiologically characterized by wellorganized tracts of myelinated axons with associated oligodendrocytes; in contrast, in HH, oligodendrocytes and myelinated fibers are rare and irregularly distributed. According to Coons et al., synaptosomal-associated protein-25 and synaptophysin immunohistochemistry show diffuse production of synapse-associated proteins analogous to normal gray matter in both nodular and diffuse patterns.⁸

In veterinary medicine, only one case report of HH has previously been published. This report describes a young adult female wirehaired pointing griffon with episodes of ataxia, disorientation, and tendency to left circling that progressed to frequent, sudden flaccid collapses lasting up to several minutes.⁵ This case shares many similarities with ours; both dogs were young adult (10–12 mo old) female hunting-breed dogs. Additionally, clinical signs were episodic and recurrent, although the clinical presentation and the main complaint for neurological consultation were slightly different. Lastly, pituitary axis dysfunction and CPP were not described in either case.

However, the present case more closely resembled the clinicopathologic behavior of the human counterpart⁶ than the case described by Cook et al.⁵ The former HH was pedunculated (parahypothalamic), a pathologic condition almost always correlated with CPP in children. On the contrary, we describe a sessile (intrahypothalamic) HH, clinically characterized, in human medicine, mainly by seizures with episodic behavioral and psychiatric problems and lack of CPP in about half of the cases.⁹ Clinical manifestations of emotional changes are quite difficult to identify in dogs, as are gelastic seizure types. However, in our case, episodes of compulsion and mentation changes were reported and eventually figured as behavioral abnormalities, exactly as described in humans.

However, because of the limited number of canine HH reports in veterinary literature, a consistent clinical comparison with the human counterpart is not possible. Thus, further cases are needed to confirm that CPP is not a key clinical finding in dogs.

Interestingly, in both cases the space-occupying nature of the HH was responsible for an enlargement of the middle fossa of the developing cranial cavity. This feature is not described in other potential differential lesions for HH in young dogs and could be a helpful hallmark during the diagnostic imaging procedure, especially when computed tomography is used for scanning the brain. MRI findings of our case report are consistent with HH human cases: a solid isointense to gray matter on T1W, slightly hyperintense on T2W images, nonenhancing lesion located in the suprasellar region. Based on the location, primary differential diagnoses for solid lesions in dogs are pituitary adenoma, meningioma, lymphoma, ependymoma, granular cell, and germ cell tumors.¹⁵ Other, less likely, differential diagnoses for suprasellar masses include craniopharyngioma, Rathke’s cleft cyst, HH, and arachnoid cyst.¹⁶ Pituitary tumors usually are isointense on T1W and have mixed isointensity and hyperintensity on T2W images, with uniform, minimal-to-strong contrast enhancement.¹⁷ Specifically, meningiomas are usually hyperintense on T2W images and uniformly isointense to gray matter on T1W images, with marked and uniform contrast enhancement, whereas craniopharyngioma and pituitary adenoma also have solid portions with homogeneous or reticular contrast uptake.¹⁸

Furthermore, hyperintensity on T1W sequence due to hemorrhage is frequent in pituitary adenoma and craniopharyngioma.¹⁶ Central nervous system lymphoma should be considered in dogs in whom a mass lesion is isointense or hyperintense on T2W sequence compared with gray matter with strong uniform contrast enhancement and perilesional edema.¹⁹ On the other hand, granular cell tumor MRI findings are mildly hyperintense on T1W and hypointense on T2W images, as opposed to other neoplasms.²⁰ As previously described in our case, imaging features of HH (isointense on T1W images and absence of contrast enhancement) could help clinicians to differentiate it from other suprasellar lesions, as already described in humans.¹¹ According to Delalande’s classification,¹³ our case could be defined as type IV HH, for which no specific surgical procedures can be recommended and a combined surgical and radiosurgical approach is necessary for complete treatment. In veterinary medicine, this type of surgical approach is still not described in literature. A transsphenoidal surgical approach is currently recommended only for pituitary tumors. Based on the site and size of our lesion, a surgical approach was not considered feasible, and radiotherapy, despite the delay in its effects, was proposed as a treatment option but refused by the owner.

Histological findings, in our case and in the previous report,⁵ were mainly characterized by discrete nodular foci of abnormally distributed neurons interspersed with glial cells, similar to what is described in human medicine. Furthermore, synaptophysin immunoreaction revealed a more crowded network of synapse-associated proteins, as in humans.⁸

Conclusion

We described clinical, MRI, and histopathological features of HH, an extremely rare disease in dogs. Specifically, MRI was helpful in determining the extent and the imaging features of the lesion. Hence, based on these findings, it would be reasonable to include HH in the differentials for young dogs with intermittent intracranial signs. Further cases are needed to confirm the unique clinical and imaging features of this disease in dogs.