Buccoliero, A. M.

Caldarella, Adele

Fiorini, P.

Noccioli, B.

Taddei, Antonio

Taddei, Gian Luigi

English

Florence Research

SummaryPharyngeal brain heterotopia is a congenital and gener-ally biologically benign lesion. In contrast to brain het-erotopia in the nose, the most common site of this le-sion, brain heterotopia in the pharynx is very rare. Pha-ryngeal heterotopic tissue can be composed of variouscomponents, i.e., astrocytes, neurons, ependyma orchoroid plexus, oligodendrocytes, retina, and, occasion-ally, neoplastic nodules. In contrast, nasal lesions areoften only composed of astrocytes. We report a case ofbrain heterotopia in the pharyngeal region, diagnosed ina newborn female infant, causing serious respiratorydistress. The infant underwent surgical excision of thelesion, and after 1 year of follow-up, she is recurrence-free. The mass, about 3 cm in diameter and showing noconnection with encephalic structures, was character-ized by numerous papillary structures and areas contain-ing stellate-like or spindle cells focally forming nodules.Moreover, there was inflammatory infiltration, whereasmitoses, hemorrhages, and necroses were absent. Im-munohistochemistry revealed a choroid plexus nature ofthe papillary formations (S-100, cytokeratins, trans-thyretin and vimentin-positive) and the presence of glialand neuronal cells in the remaining areas (glial fibrillaryacidic protein, neuron-specific enolase, neurofilaments,synaptophysin, and S-100 positive). This case reportconfirms that the presence of choroid plexus is not un-common and that pharyngeal brain heterotopia is usual-ly benign.Key words: Brain Heterotopia – Pharynx – Nasalglioma – Respiratory distress – ImmunohistochemistryAbbreviations: CK = Cytokeratin, GFAP = Glial fibril-lary acidic protein, NSE = Neuron-specific enolase,VIM = Vimentin, SY = Synaptophysin, NF = Neurofila-ment, PBS = Phosphate-buffered saline solution, HE =Hematoxylin-eosinIntroductionLesions composed of brain tissue occurring in the headand neck region, i.e., soft palate, pharynx, paranasalsinus, and nasal district have already been reported [17].Most of these lesions, the so-called nasal gliomas, arefound in or about the nose [16]. Nasal glioma has beenestimated to occur in one in 20,000 to 40,000 live births[15]. In contrast, Bossen and Hudson [2], and Uemuraet al. [27] reported on 18 and 17 cases of heterotopicbrain tissue in the pharynx and the soft palate, respec-tively. In addition, four new cases have recently beendescribed [20].Heterotopic brain tissue is frequently diagnosed in ei-ther nasal or non-nasal location in newborn infants,whereas it is only rarely found in adults [9, 21].Respiratory distress may be a characteristic symp-tom; nasal obstruction and epistaxis occur in intranasallesions; cerebrospinal fluid rhinorrhea and meningitisTeaching CaseBrain Heterotopia in Pharyngeal Region.A Morphological and Immunohistochemical StudyAnna Maria Buccoliero1, Adele Caldarella1, Bruno Noccioli2,Patrizio Fiorini3, Antonio Taddei4, Gian Luigi Taddei11Dipartimento di Patologia Umana e Oncologia, Università degli Studi di Firenze, Firenze,2U.O. Chirurgia Pediatrica II and 3U.O. Neonatologia e Patologia Neonatale,Azienda Ospedaliera Anna Meyer, Firenze4Dipartimento di Area Critica Medico-Chirurgica Sezione Chirurgia Generale e D.C.,Università degli Studi di Firenze, ItalyPathol. Res. Pract. 198: 59–63 (2002) 0344-0338/02/198/1-59 $15.00/0PATHOLOGYRESEARCH AND PRACTICE© Urban & Fischer Verlaghttp://www.urbanfischer.de/journals/prpAddress for correspondence: Gian Luigi Taddei, Diparti-mento di Patologia Umana e Oncologia, Università degli Studidi Firenze, Viale G.B. Morgagni, 85,  50134 Firenze, Italy.Tel.: +39+55-413756, Fax: +39+55-4379868.E-mail: gl.taddei@unifi.itFig. 1. Magnetic resonance scans of head-neck: a parenchy-matous lesion of about 3 cm in diameter in left pharyngeal region.are occasionally observed in cases of intracranial exten-sion. Furthermore, one can encounter obstruction of thelachrymal apparatus or visual impairment in subcuta-neous external nasal location [8].In general, biologically heterotopic brain tissue in thehead and neck region is a benign lesion only occasional-ly recurring (4–10% of the cases) [23] in cases of in-complete excision. Nevertheless, this lesion can lead tosevere respiratory distress and death particularly in new-born infants [3, 6, 25].In contrast to the most common nasal gliomas, oftenexclusively composed of glial cells, heterotopic pharyn-geal brain tissue can show ependyma, choroid plexus,and retinal or, rarely, neoplastic components [2].We report an additional rare case of heterotopic pha-ryngeal-parapharyngeal brain tissue in a newborn infant.Clinical HistoryA two-day-old female newborn infant was admitted to apediatric hospital for severe respiratory distress. Preg-nancy was uncomplicated. The child was delivered bycesarean section because of placental insufficiency. Be-fore the symptoms appeared, the infant had been foundto be healthy, weighing 3280 gr. with an Apgar score of9 and 10 at the first and the fifth minute after birth, re-spectively. However, in the course of time, the infantbegan suffering from increasing respiratory distress ne-cessitating tracheostomy. A physical examination re-vealed a pearly gray round mass localized behind andabove the uvula. The child underwent a radiography ofthe neck region revealing a left pharyngeal-parapharyn-geal mass. Magnetic resonance imaging gave further ev-idence of the presence of a 3 cm lesion located betweenRosenmuller’s recess and the neurovascular bundle ofthe neck (Fig. 1). There was no connection between thelesion and cranial cavity. Tissue obtained from a biopsywas diagnosed as brain heterotopia. The mass was com-pletely excised. No postoperative complications oc-curred, and after 1 year of follow-up, the child is aliveand well with no signs of recurrence.Materials and MethodsThe specimen was fixed in 10% buffered neutral formalin, ad-equately sampled, and embedded in paraffin. Some sectionswere stained with hematoxylin-eosin (HE) for morphologicalevaluation, whereas further sections were mounted on electro-static slides and used for immunohistochemical study. The pri-mary antibodies used were as follows: monoclonal antibodyagainst Ki-67 (Mib-1), cytokeratin (CK), glial fibrillary acidicprotein (GFAP), neuron-specific enolase (NSE), vimentin(VIM), and synaptophysin (SY); multiclonal antibody againstneurofilaments (NF); polyclonal antibody against transthyretin(TTR), and S-100 protein (for clone, dilutions, and sources ofantibodies, Table 1). Sections designated for immunohisto-chemistry were air-dried overnight at 37 °C, deparaffinizedthrough xylene, and dehydrated through graded alcohol. Endo-geneous peroxidase activity was blocked by immersing thespecimens in a solution of 0.5% H2O2. To recover antigenicity,slides incubated with TTR were treated with protease, whereasslides incubated with Mib-1, CK, GFAP, NSE, NF, SY andVIM antibodies were placed in a citrate buffer (10 mM, pH6.0), followed by microwave antigen enhancement (300 W for40 min). The sections were cooled down to room temperature,washed with phosphate-buffered saline solution (PBS, pH 7.4)and treated with normal horse serum (LAB VISION Corpora-tion, Fremont, California) to reduce non-specific antibodybinding. After extensive washing in PBS, the sections were in-cubated with biotinylated anti mouse IgG (LAB VISION) andthen with streptavidin-biotin-peroxidase complex reagent(LAB VISION). After extensive washing with PBS, the slideswere treated with 3,3′-diaminobenzidine-hydrogen peroxide(BioGenex, San Ramon, California) as a final indicator, andlightly counterstained with Mayer’s hematoxylin. Negativecontrol experiments were done by replacing the primary anti-bodies with non-immune mouse serum at an equivalent pro-tein concentration.ResultsLight microscopy revealed various morphological fea-tures. Papillary structures sometimes inside cysticspaces and lined by cuboidal or cylindrical cells wereidentifiable (Fig. 2A). In addition, within thin fibro vas-cular stroma, we observed large areas characterized by60 · A. M. Buccoliero et al.mFig. 2. The mass shows a three-phasic pat-tern: papillary structures lined by cuboidalor cylindrical epithelium (A), areas charac-terized by stellate or spindle cells in inflam-matory infiltration (B) sometimes formingnodules (C) (HE staining). bFig. 3. In the papillary structures, immuno-histochemistry for TTR yielded positive re-sults.bFig. 4. In non-papillary areas, immunohis-tochemistry revealed both neurons and glia(A: HE; B: SY; C: NF; D: GFAP).glioma, many authors support the theory that defects inthe developing skull cause an encephalocele-like condi-tion [2]. This hypothesis, postulated to explain brainheterotopia in the lungs [12], is occasionally supportedby the presence of bone defects [2, 19, 28]. The develop-mental abnormality and the biological benignity of theselesions are widely accepted. Consequently, the term“glioma”, used in particular for nasal lesions, is ques-tionable so that the term “cerebral heterotopia” has re-cently been proposed for this lesion [4]. Nevertheless,three previously published cases of non-nasal hetero-topic brain tissue exhibited neoplastic areas [2, 11, 16].Lee et al. reported a case of a melanotic neuroectoder-mal tumor appearing simultaneously with brain hetero-topia in the oropharynx [16]; Gold et al. documented thepresence of mixed oligo-astrocytoma in a palatal lesionassociated with a cleft palate [11], and Bossen and Hud-son reported an oligodendroglioma arising in hetero-topic brain tissue in the soft palate and nasopharynx [2].In addition, Chan and Lau reported a case of frontal lobeastrocytoma connected with an astrocytic lesion in thenasal cavity in a 34-year-old man [5]. However, Chanand Lau hypothesized that the nasal lesion derived fromdownward extension of the cerebral astrocytoma ratherthan from a neoplastic transformation of a nasal glialheterotopia with intracranial extension, or from a coex-istence of two independent lesions. Thus, in brain het-erotopia, neoplastic components are reported to occurexclusively in non-nasal location.An additional difference between nasal and non-nasallocation lies in the presence of various components innon- nasal location, whereas nasal lesions are exclusive-ly composed of glial cells in general. In pharyngealthe presence of stellate-like cells or spindle cells(Fig. 2B); focally, they formed nodules of various sizeand were intersected by fibrous tissue septa (Fig. 2C).Diffuse inflammatory infiltration was visible, whilethere were no areas of necrosis, hemorrhage, mitotic fig-ures, and atypical cells.The results obtained by immunohistochemistry aresummarized in Table 1. In the papillary component, im-munohistochemistry for CK, S-100, TTR (Fig. 3) andVIM yielded positive results, suggesting a choroidplexus nature. The remaining areas were positive forVIM, S-100, NSE, SY, NF and GFAP, disclosing bothneurons and astrocytes (Fig. 4). The proliferation rate,evaluated by monoclonal antibody Mib-1, was low inthe heterotopic cells.DiscussionAs early as 1900, Schmidt [24] hypothesized that nasalglioma originates from the herniation of neuroectoder-mal tissue. In the embryo, between the nasal and frontalbones, there exists a membrane, the so-called fonticulusnaso-frontalis, which develops into foramen cecum.Dural and neuroectodermal tissues are present [1, 13] inthe space delimited by fonticulus naso-frontalis and inthe cartilaginous capsule of external nose during thefirst weeks of embryonal development. The closure ofthe craniofrontal sutures, before its complete intracra-nial retraction, would cut and sequestrate a mass of neu-roectodermal tissue. The origin of brain heterotopia inpharyngeal and soft palate regions is less obvious thanthat of nasal glioma [2]. Nevertheless, similar to nasal62 · A. M. Buccoliero et al.Table 1. Clone, dilution, and source of antibodies used and immunohistochemical resultsAntibody Clone Dilution Source Papillary Non papillaryareas areasMib-1 Mib-1 1:80 IMMUNOTECH – –(Marseille, France)CK AE1/AE3 1:200 BioGenex + –(San Ramon, California)GFAP ZCG29 Prediluted Zymed Laboratories – +(San Francisco, California)NSE MIG-N3 Prediluted BioGenex – +(San Ramon, California)S-100 – 1:2000 Dako + +(Glostrup, Denmark)VIM V9 1:2000 BioGenex + +(San Ramon, California)NF DA2; FNP7; RMb020.11 1:20 Zymed Laboratories – +(San Francisco, California)SY Snp 88 Prediluted BioGenex – +(San Ramon, California)TTR – 1:900 Novocastra + –(Newcastle, United Kingdom)brain heterotopia, besides the constant presence of astro-cytes, ependyma or choroid plexus, neurons, oligoden-droglia, retina-like structures are detectable [2]. In con-trast, in addition to astrocytes, cases with neuronal orleptomeningeal cells in nasal location have only rarelybeen reported [10, 18, 22].In this case, choroid plexus is obvious and is docu-mented immunohistochemically by TTR positivity. Inthe brain, TTR is uniquely synthesized by choroidplexus epithelium, representing its most typical andmajor biosynthetic product [7, 14, 26].Choroid plexus represents the most interesting fea-ture of pharyngeal brain heterotopia. Bossen, reviewingthe previously described cases, ascertained the presenceof ependyma or choroid plexus in the pharyngeal andsoft palate regions in 14 of 18 cases (78%) [2], a findingsupported by our case, indicating that their presence isnot uncommon.Identification of neuroglial tissue in the head andneck region allows for a variety of diagnostic possibili-ties: heterotopic tissue, encephalocele or teratoma [22].A preoperative radiological study with a water solublecontrast agent, careful histopathological examinationsof the entire specimen, and immunohistochemical eval-uations are necessary to recognize the heterotopic natureof this rare and frequently benign lesion, sometimes pre-senting with severe symptoms.References1. Bianchi PM, De Vincentiis G, Andriani G, Masi R (1985)Mixed nasal glioma: clinico-statistical contribution. ActaOtorhinolaryngol Ital 5: 533–5402. Bossen EH, Hudson WR (1987) Oligodendroglioma aris-ing in heterotopic brain tissue of the soft palate and na-sopharynx. 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Uemura T, Yoshikawa A, Onizuka T, Hayashi T (1999)Heterotopic nasopharyngeal brain tissue associated withcleft palate. Cleft Palate Craniofac J 36: 248–251 28. Wakai S, Nakamura K, Arai T, Nagai M (1983) Extracere-bral neural tissue mass in middle cranial fossa extendinginto the oropharynx in a neonate. J Neurosurg 59: 692–696Received: September 11, 2001Accepted in revised version: November 12, 2001Pharyngeal Brain Heterotopia · 63

Brain heterotopia in pharyngeal region. A morphological and immunohistochemicalstudy.

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Brain heterotopia in pharyngeal region. A morphological and immunohistochemicalstudy.

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