Case 3 -

Choroid Plexus Xanthogranuloma (Bilateral Xanthogranulomata of the Choroid Plexus Glomera Choroidea) Gregory N. Fuller M.D. Anderson Cancer Center Houston, TX

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Clinical History A 60-year-old man presented with a right upper lobe lung mass and bilateral mass lesions of the lateral ventricles. Diagnosis: Choroid plexus xanthogranuloma (bilateral xanthogranulomata of the choroid plexus glomera choroidea) Discussion Incidental mass lesions of the choroid plexus The two incidental mass lesions of the choroid plexus with which every pathologist should be familiar are cystic degeneration and xanthogranuloma [1]. Cystic degeneration is a common accompaniment of aging and although often visually striking has no pathologic significance. Only exceptionally rarely does cystic change reach a size capable of causing obstructive hydrocephalus. Xanthogranuloma of the choroid plexus occurs less frequently than cystic change but is still relatively common. In most cases the lesions are small, only a few millimeters in diameter, and typically exhibit a vivid tan-to-yellow color on gross examination. Cases with recent hemorrhage are mottled black and yellow on cut section. Histologic Features The most striking histologic feature of choroid plexus xanthogranuloma is the conspicuous presence of cholesterol clefts. Upon closer microscopic examination, prominent multinucleated giant cells are seen attempting to engulf the cholesterol crystals. Recent and remote hemorrhage with hematoidin and hemosiderin deposition is another characteristic feature and may provide an etiologic clue as discussed below. A number of associated reactive changes are also typically seen, including foamy macrophage infiltration, fibrosis and secondary calcification. In contrast to solitary choroid plexus metastasis, overtly malignant cells are not seen. Histologic Features of Choroid Plexus Xanthogranuloma Cholesterol crystal clefts Multinucleated giant cells of foreign body-type Recent hemorrhage Remote hemorrhage with hematoidin and hemosiderin deposition Macrophage infiltration Fibroblast proliferation and fibrosis Calcification Etiology Some neuropathologists favor dividing the xanthomatous lesions of the choroid plexus into two categories: xanthomas and xanthogranulomas [2]. Xanthomas are composed purely of foamy lipid-laden macrophages, whereas xanthogranulomas have, in addition, prominent hemosiderin deposition and cholesterol crystals with the typical associated foreign body-type giant cell reaction. This distinction has etiologic connotations: at least one study has reported an association of xanthomas with hyperlipidemia, analogous to systemic xanthomas arising in a similar clinical context. In contrast, there is no association between hyperlipidemia and choroid plexus xanthogranulomas and their origin and pathophysiology are obscure. One hypothesis is that the initiating event is an intra-choroid hemorrhage, which is followed by red blood cell breakdown, cholesterol crystal formation, giant cell reaction, hemosiderin deposition, calcification and fibrosis. Although many investigators have argued that "cholesterol granuloma" is a more appropriate designation, the term "xanthogranuloma" is firmly entrenched in the literature and in the neuropathologist's lexicon. Incidence, location and treatment The xanthogranulomata seen in the present case were incidental findings. Autopsy series have noted incidental xanthogranulomas of the choroid plexus in 1-7% of the population [3, 4] . Symptomatic choroid plexus xanthogranuloma is relatively uncommon but does occur [5, 6, 7, 8, 9] . Most patients present with obstructive hydrocephalus and the attendant general signs and symptoms of increased intracranial pressure, although more unusual clinical manifestations, such as parosmia and parageusia, have occasionally been noted [8]. Treatment consists of surgical resection to relieve the hydrocephalus and mass effect. The most common anatomic location for xanthogranuloma within the choroid plexus is in the largest tuft, which is located in the atrium of the lateral ventricle and is called the glomus choroideum (pl. glomera choroidea) [10]. Incidental glomus choroideum xanthogranulomas are frequently bilateral, as in the present case, but may also be unilateral. Symptomatic xanthogranulomas most commonly arise in the lateral ventricle choroid plexus of adults. However, symptomatic xanthogranulomas have also been reported in the third ventricle [11, 12] and in children, in which they are often bilateral [13, 14] . Differential Diagnosis: Isolated unilateral or bilateral metastasis to the choroid plexus Isolated metastasis to the choroid plexus (CNS metastatic disease limited to the choroid plexus in the absence of parenchymal metastasis) is very rare with an estimated incidence of only 0.14% of all cerebral metastases [15, 16, 17] . Of all systemic primary cancers, renal cell carcinoma in particular shows a propensity for choroid plexus metastasis [17]. Isolated choroid plexus metastasis as the presenting condition in the absence of a known primary is exceptionally rare. Bilateral choroid plexus xanthogranuloma is far more common than isolated bilateral choroid plexus metastasis and most cases of bilateral choroid plexus xanthogranuloma are usually recognized by the radiologist. In unilateral xanthogranuloma cases, the possibility of solitary metastasis is often entertained, particularly in patients who have a history of a systemic malignancy. Even in this setting, however, xanthogranuloma is more common than solitary metastasis to the choroid plexus. Nevertheless, surgery is sometimes performed on suspicion of metastasis from a known or unknown primary tumor, and it is therefore incumbent upon the surgical pathologist to be familiar with the histopathologic features of this entity. Similarly, at autopsy, upon sectioning the brain and seeing a large yellow-black mass in one or both glomera choroidea, the pathologist's first thought is likely to be metastasis, particularly if the patient has a history of cancer. An awareness of choroid plexus xanthogranuloma, however, can temper this rush to judgment. Histologic sections provide an unequivocal diagnosis. Other intraventricular mass lesions Xanthogranuloma is one of limited number of circumscribed mass lesions that are confined to the intraventricular anatomic compartment and that are treated primarily by surgical resection [1]. The principal entities in the differential diagnosis of a circumscribed intraventricular mass lesion are listed in the Table. Intraventricular Mass Lesions Choroid plexus papilloma / atypical papilloma / carcinoma Intraventricular (choroid plexus) meningioma Isolated metastasis to the choroid plexus Xanthogranuloma of the choroid plexus Chordoid glioma of the 3rd ventricle Colloid cyst of the 3rd ventricle Central neurocytoma Ependymoma Subependymoma Subependymal giant cell astrocytoma Fetus (intracranial intraventricular fetus-in-fetu) Equine Choroid plexus Xanthogranuloma Mass lesions of the choroid plexus identical to the xanthogranulomas seen in humans frequently occur in horses, where they are commonly referred to as cholesterol granulomas or cholesterinic granulomas [18, 19, 20, 21, 22] . They are in fact more common in horses than in humans and are age-associated with an incidence of 15-20% in older horses. As in humans, equine choroid plexus xanthogranulomas are often bilateral. A majority, as in humans, are asymptomatic, but they may occasionally attain massive size, filling both lateral ventricles. Afflicted horses typically present with seizures or with gait and balance disturbances secondary to obstructive hydrocephalus [18, 19, 20, 21, 22] . Choroid plexus xanthogranulomas have rarely been reported in other animal species, such as the fat-tailed dwarf lemur [23], but in no other species is xanthogranuloma as common as in horses and humans. The explanation for why humans and horses share this peculiar predilection for choroid plexus xanthogranulomas is unknown. Species Incidence of Choroid Plexus Xanthogranuloma Humans 1-7% Horses 15-20% Other species rare isolated case reports References Fuller GN, Goodman JC. Practical Review of Neuropathology. Philadelphia: Lippincott Williams & Wilkins, 2001. Muenchau A, Laas R. 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Lee JT, Miller CA, MacDonald C and Allman J M. Xanthogranuloma of the choroid plexus in the fat-tailed dwarf lemur (Cheirogaleus medius). Am J Primatol 38:349-355, 1996.