Abstract. A 35-year-old woman presented with dyspnea,recurrent laryngitis and gastroesophageal reflux disease.Laryngoscopic examination revealed a yellow lesion on theanterior site of the left true vocal cord. No abnormal lesions werefound in other portions of the larynx. The lesion was biopsied anda histological examination showed numerous foamy cellsdiffusely presented in the stroma of the specimen. Overlyingsquamous epithelium did not show cellular atypia. On the basisof histological appearance, the possible differential diagnosisincluded xanthomatous lesion, granular cell tumor or epithelialneoplasia. CD68, S-100 protein and cytokeratin immuno-reactivities were investigated. Immuno-histochemically, foamycells were positive for CD68, indicating a histiocytic origin.

Xanthoma is a localized collection of foamy histiocytescontaining lipids. The lesions are yellowish and commonlyoccur in skin, soft tissue and stomach (1). To date, to the bestof our knowledge, only one case of laryngeal xanthomahaving the characteristic feature of pedunculated polypoidappearance has been reported (2). Recently, a case of solitaryflat laryngeal xanthoma diagnosed as a dysplastic lesion onlaryngoscopic examination in a woman with normal values forblood chemistry tests and without cutaneous xanthomas wasencounted. Possible diagnoses and immunohistochemicalprofiles are also discussed.

Case report

A 35-year-old woman with dyspnea, recurrent laryngitis andGERD (gastroesophageal reflux disease) history was

admitted to the Department of Otolaryngology of theCampus Bio-Medico University Hospital, Italy. Bloodchemistry tests, including plasma cholesterol, showednormal values and cutaneous xanthomas were not found.Fiber-optic laryngoscopy revealed a yellow lesion in theanterior site of the left true vocal cord (Figure 1A). Noabnormal lesions were found in other portions of the larynx.The lesion was biopsied in microlaryngoscopy and ahistological examination was performed.

Grossly, the lesion was soft with a yellowish cut surface.Histologically, clusters and sheets of numerous foamy cellswere diffusely present in the stroma of the biopsy specimen(Figure 1B, C). Overlying squamous epithelium did notshow cellular atypia. Mild acanthosis was seen. None of thehistiocytes or giant cells showed cellular atypia. Perivascularinfiltration of inflammatory cells was present.

Results

Unless otherwise stated, all reagents were from Dako Cyto-mation, Inc. (Carpinteria, California). Immunohisto-chemical studies was performed on formalin-fixed paraffin-embedded sections using the streptavidin-biotin method.

All foamy cells were strongly immunopositive for CD68(1/200) (Figure 1D), while S-100 protein (1/500) andAE1/AE3 cytokeratin (1/50) were negative.

Discussion

We report a case of laryngeal xanthoma in a normolipemicyoung woman. Solitary laryngeal xanthoma is a very rarecondition and may be diagnosed as hyperkeratosis, dysplasticor carcinomatous lesions on laryngoscopic examination.

The foamy cells found in the laryngeal mucosa of our casewere morphologically typical. However, to clarify the realorigin of the cells observed in this lesion, an immuno-histochemical study was performed. On the basis ofhistological appearance, the possible differential diagnosiscould include a xanthomatous lesion, a granular cell tumor

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Correspondence to: Giuseppe Perrone, MD, Surgical Pathology,University of Campus Bio Medico, Via Emilio Longoni 47, 00155Rome, Italy. Tel: +39 06 22541719, Fax: +39 06 233 238 694, e-mail: g.perrone@unicampus.it

Key Words: Xanthoma, larynx, immunohistochemistry, differentialdiagnosis.

in vivo 21: 119-122 (2007)

Immunohistochemistry and Differential Diagnosis of a Solitary Flat Laryngeal Xanthoma: A Case Report

GIUSEPPE PERRONE1, MARIAGIOVANNA ZAGAMI1, MANUELE CASALE2, FABRIZIO SALVINELLI2, SERGIO MORINI3 and CARLA RABITTI1

1Surgical Pathology, 2Department of Otolaryngology and 3Department of Biomedical Research, Campus Bio-Medico University, Rome, Italy

0258-851X/2007 $2.00+.40

or an epithelial neoplasia (3, 4). We subsequently investigatedimmunoreactivity for CD68, S-100 protein and cytokeratin.Granular cell tumor is a relatively benign hamartomatouslesion, uncommon, but not rare in larynx, which showspositive immunoreaction for S-100 protein because of itsnervous origin (4). On the other hand, some carcinomas showclear cell pattern at microscopic examination because of theaccumulation of lipid or glycogen in the cell cytoplasm andare also positive for cytokeratin expression.

The immunophenotype of the present lesion was negativefor the S-100 protein and cytokeratin and positive for CD68,indicating a histiocytic origin. After the identification of thehistiocytic nature of our lesion, we considered the possiblelaryngeal diseases containing numerous histiocytes, e.g.verruciform xanthoma, xanthoma disseminatum andxanthoma confined to the larynx.

Verruciform xanthoma is a relatively uncommon lesionand occurs in the oral cavity and respiratory tract withhistological features of a papillary or verrucous projectionof surface squamous epithelium and xanthoma cellsrestricted to the connective tissue papillae between theepithelial rete ridges (5). In the current case, we ruled outverruciform xanthoma because of the histologicalappearance of non-papillary squamous epitheliumobserved on the surface. Xanthoma disseminatum is anexceedingly rare disorder (6). In xanthoma disseminatum,the skin is always involved and xanthomas are also presentin other organs (6). We ruled out xanthoma disseminatuminvolving the larynx because of the absence of xanthomason the skin during hospitalization. Subsequently, weregarded the present case as a solitary xanthoma confinedto the larynx.

in vivo 21: 119-122 (2007)

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Figure 1. Fiber-optic laryngoscopy showed a yellow lesion in the anterior site of the left true vocal cord. No abnormal lesions were found in other portions ofthe larynx (A). At histological examination, clusters and sheets of numerous foamy cells were diffusely present in the stroma of the biopsy specimen. Theoverlying squamous epithelium did not show cellular atypia. Mild acanthosis was seen (B, original magnification 100X). None of the histiocytes and giant cellsshowed cellular atypia. Perivascular infiltration of inflammatory cells was present (C, original magnification 200x). Immunohistochemical studies performedon formalin-fixed paraffin-embedded sections revealed that the foamy cells were strongly immunopositive for CD68 (D, original magnification 400x).

In 1999, Matsumoto et al. (2) reported for the first time,a case of solitary laryngeal xanthoma having thecharacteristic feature of pedunculated polypoid appearance.To the best of our knowledge we present the first case ofsolitary flat laryngeal xanthoma.

Pure xanthomas are regarded as the tissue expression of anabnormality of lipid metabolism and they are often associatedto hyperlipemia (7). However, in the current case, bloodchemistry tests, including plasma cholesterol, showed normalvalues. The etiology of xanthoma in some visceral sites has notyet been established. For example in the stomach, althoughthe xanthoma cells contain cholesterol with or without neutralfat, there is no linkage to any type of hyperlipemia (8). Sincegastric xanthomas appear to be more common in patients withgastritis, gastric ulcer and with duodeno-gastric reflux aftergastrectomy, mucosal damage has been presumed to play amajor role in their pathogenesis (9-11).

As previously mentioned, our normolipemic patientreported a history of GERD and recurrent laryngitis.Recent studies indicated that GERD was implicated in 40to 75% of patients with both laryngeal symptoms andlaryngoscopic evidence of laryngeal pathology (12, 13). Inour patient, the gastroesophageal reflux could havecontributed to the development of laryngeal xanthoma. Thefocal mucosal damage that follows chronic inflammationcould produce lipid-containing debris, eventuallyphagocytized by histiocytes forming foam cells.

References

1 Rosai J: Skin. In: Surgical Pathology. Rosai J and Ackerman's(eds.). Edinburgh-New York 9th edition, Mosby, pp. 185-186,2004.

2 Matsumoto T, Nobukawa B, Kobayashi K, Watanabe M,Hosokawa A, Tomaru K and Ichikawa G: Solitary polypoidxanthoma in the larynx. Histopathology 34: 475-477, 1999.

3 Al-Nafussi AI, Azzopardi JG and Salm R: Verruciformxanthoma of the skin. Histopathology 9: 245-252, 1985.

4 Toprak M, Oz F, Oktem F, Acioglu E and Yilmaz S: Granularcell tumour of the larynx. J Otolaryngol 34: 363-365, 2005.

5 Mostafa KA, Takata T, Ogawa I, Ijuhin N and Nikai H:Verruciform xanthoma of the oral mucosa: a clinicopathologicalstudy with immunohistochemical findings relating topathogenesis. Virchows Arch A Pathol Anat Histopathol 423:243-248, 1993.

6 Moloney JR: Xanthoma disseminatum: its otolaryngologicalmanifestations. J Laryngol Otol 93: 201-210, 1979.

7 Parker F: Xanthomas and hyperlipidemias. J Am AcadDermatol 13: 1-30, 1985.

8 Kaiserling E, Heinle H, Itabe H, Takano T and Remmele W:Lipid islands in human gastric mucosa: morphological andimmunohistochemical findings. Gastroenterology 110: 369-374,1996.

9 Mast A, Eelwaut A, Mortier G et al: Gastric xanthoma. Am JGastroenterol 65: 311-317, 1976.

10 Kimura K, Hiramoto T and Buncher CR: Gastric xanthelasma.Arch Pathol 87: 110-117, 1969.

11 Domellof L, Eriksson S, Helander HF and Janunger KG: Lipidislands in the gastric mucosa after resection for benign ulcerdisease. Gastroenterology 72: 14-18, 1977.

12 Koufman JA: The otolaryngologic manifestations of gastro-esophageal reflux disease (GERD): a clinical investigation of225 patients using ambulatory 24-hour pH monitoring and anexperimental investigation of the role of acid and pepsin in thedevelopement of laryngeal injury. Laryngoscope 101: 1-78, 1991.

13 Deveney CW, Benner K and Cohen J: Gastroesophageal refluxand laryngeal disease. Arch Surg 128: 1021-1027, 1993.

Received October 6, 2006Accepted November 7, 2006

Perrone et al: Flat Laryngeal Xanthoma: A Case Report

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