Bevel: Case Report

Oral Hairy Leukoplakia in a Patient with Systemic Primary Amyloidosis: A Case Report

Jeane de F‡tima Correia-Silva, Renata Gon¨alves Resende, Fernanda Maia Lodi, Brendan Conn, Ricardo Alves Mesquita, Ricardo Santiago Gomez

------------------------------------------------------------------------------------------------------------------------------------------------

Abstract

Oral hairy leukoplakia is characterized by an asymptomatic white plaque on the lateral borders of the tongue. It is associated with immunodeficiency, principally to Human Immunodeficiency virus infection, but it has also been reported in patients with other immunosuppressed states. A 48-year-old man with primary amyloidosis was referred to evaluate a white plaque on the tongue. Based on the patientÕs clinical presentation, medical history, and localization of the oral lesion, differential clinical diagnosis included amyloidosis, oral hairy leukoplakia, idiopathic leukoplakia, hyperplastic chronic candidiasis, and uremic stomatitis. The diagnosis of oral hairy leukoplakia was confirmed by histopathological analysis and in situ hybridization showing Epstein-Barr virus. This is an unusual clinical presentation of oral hairy leukoplakia.

 

Keywords: Amyloidosis; Autologous; EBV; Oral Hairy Leukoplakia; Stem Cell; Transplantation.

 

Jeane de F‡tima Correia-Silva, Renata Gon¨alves Resende, Fernanda Maia Lodi, Brendan Conn, Ricardo Alves Mesquita, Ricardo Santiago Gomez. Oral Hairy Leukoplakia in a Patient with Systemic Primary Amyloidosis: A Case Report. International Journal of Oral & Maxillofacial Pathology; 2014:5(3):07-11. ©International Journal of Oral and Maxillofacial Pathology. Published by Publishing Division, Celesta Software Private Limited. All Rights Reserved.

 


Introduction

Amyloidosis is a disease entity defined by the presence of extracellular accumulation at systemic or organ-specific level of insoluble low molecular weight protein fibrils manifesting a beta pleated sheet configuration and a characteristic staining pattern.1 Amyloidosis of the oral cavity is rare.2 Oral hairy leukoplakia (OHL) is characterized by an asymptomatic white plaque on the lateral borders of the tongue. This plaque has a ßat, corrugated, or hairy surface that cannot be removed through scraping. OHL is associated with immunodeficiency, principally to Human Immunodeficiency virus (HIV) infection, but it has also been reported in patients with other immune suppressed states.3 Prevalence of OHL in HIV infected Brazilian adults is reported to be 28.8%.4 The etiology is associated with reactivation of (Epstein-Barr virus) EBV infection and the lesions occur primarily on the lateral borders of the tongue. Other rare locations are ventral or dorsal portion of the tongue, labial mucosa, ßoor of the mouth, and soft palate.5 The purpose of this paper is to present an unusual case of OHL in a patient with systemic primary amyloidosis and discusses on differential diagnoses.

 

Case Report

A 48-year-old man was referred by the Stem Cell Transplantation Unit of the Hospital das Cl’nicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil to the Oral Medicine Clinic of the School of Dentistry to evaluate a tongue lesion. The patient had noticed the appearance of the lesion three months earlier. Further, he noted that brushing did not remove the lesion and that it was growing. His previous medical history revealed muscle weakness of the lower limbs, which involved unsteadiness when walking and climbing stairs, in October 2010. In February 2011, the patient developed edema of the lower limbs. Extensive clinical research conducted in collaboration with the different medical services led to suspected amyloidosis. Histological analyses showed renal amyloidosis with deposition of lambda light chains. The patient used prednisone 60 mg/day for 13 days, and two doses of methotrexate (50 mg each time) in May 2011. There was, however, no clinical improvement in the systemic condition. In June 2011, the patient received dexamethasone (40 mg/day, for 4 days) and cyclophosphamide (500 mg/week). The patient was a nonsmoker with no history of recreational drug use or risk factors for HIV. Intra-oral inspection revealed the presence of multiple asymptomatic white plaques with regular borders and irregular surface located in the tongue with extension to the ventral and dorsal surfaces. The plaques were not removable when scraped (Fig 1).

 

Blood tests showed that levels of uric acid and electrolytes were normal; however, the patients presented a low platelet count (Table1). The patient was tested for Hepatitis C virus (HCV), Hepatitis B virus (HBV), Human T lymphotropic virus type I (HTLV I), Human T lymphotropic virus type II (HTLV II), Herpes Simplex virus type I (HSV I), Herpes Simplex virus type II (HSV II), EBV, and HIV. Results showed that the patient was EBV seropositive (IgG).

 

Figure 1: Multiple asymptomatic adherent white plaques with regular borders and irregular surface located on the ventral surface of the tongue.

 

Exfoliative cytological examination of the lesion was carried out, and Candida (sp) was identified. Oral candidiasis was treated with topical nystatin for 15 days. Despite antifungal therapy, the lesion did not present clinical improvement; thus, an incisional biopsy was performed from the dorsal tongue. Histopathological analysis revealed mucosa exhibiting hyperkeratosis and acanthosis (Fig. 2A). Ballooning degeneration was observed in the upper layer of the epithelium; in addition, we observed a vacuolated cytoplasm with small, round, deeply basophilic nuclei surrounded by a clear narrow halo. The reaction for EBV detection was carried out using an EBER probe for EBV and the corresponding anti-fluorescein antibody for localization (Novocastra Laboratories, United Kingdom) following the manufacturerÕs instructions. The in situ hibridization for EBV showed strong staining of keratinocytes (Figs. 2B and 2C). Thus, a diagnosis of OHL was made.

 

 


Figure 2: A) Histopathological analysis showed tongue mucosa exhibiting hyperkeratosis, acanthosis, and ballooning degeneration in the upper layer of the epithelium (hematoxylin-eosin, 50× original magnification); B) In situ hybridization for EBV (EBER) showing strong staining of keratinocytes (in situ hybridization, 50× original magnification); C) In situ hybridization for EBV (EBER) (in situ hybridization, 400× original magnification).

 


The patient underwent autologous hematopoietic stem cell transplantation in February 2012 after receiving prophylactic acyclovir (800 mg/day) before the transplantation. Treatment with the immunosuppressant drug was suspended 30 days after the transplantation, and the patient showed signs of early OHL remission. The patient was disease free 6 months after the transplantation (Fig. 3).

 

Discussion

Based on the patientÕs clinical presentation, medical history, and localization of the oral lesion, differential clinical diagnosis included amyloidosis, OHL, idiopathic leukoplakia, hyperplastic chronic candidiasis, and uremic stomatitis.

Figure 3: Clinical presentation of the tongue showing complete regression of the lesion 6 months after autologous hematopoietic stem cell transplantation.

Amyloidosis of the tongue is generally secondary to systemic disease and is characterized by extracellular deposition of amyloid fibrils derived from the circulating acute-phase reactant serum amyloid A protein.1,2 In the tongue, amyloidosis can result in macroglossia, tongue protrusion, and dysphagia. Raised white plaque or yellow nodules can occur, and these are predominately along the lateral border.2 The histopathological features found in the biopsy ruled out this diagnosis.


 

Table 1: Hematological and biochemical profile of the patient

White blood cells

10.100/mm3

Neutrophils

7.676/mm3

Lymphocytes

1.818/mm3

Mononuclear

505/mm3

Hemoglobin 

13.1 g/dL

Hematocrit

38.9%

Platelets 

111,000/mm3

Uric acid

5.3 mg/dL (normal = 3.4Š7 mg/dL)

Alkaline phosphatase

57 U/L (normal = 40Š129 U/L)

Potassium

4.15 mEq/L (normal = 3.5Š5.1 mEq/L)

Phosphor

3,6 mg/dL

Ca (Calcium)

9.2 mg/dL

 


Another less probable diagnostic hypothesis was idiopathic leukoplakia. This is a common white lesion of the oral cavity, which carries a recognized risk of malignant transformation.6 Leukoplakia is generally associated with tobacco habits and mainly affects the buccal mucosa and tongue sites6; however, idiopathic leukoplakia can be found where no etiology is apparent.7 The current patient was a non-smoker. In the current case, chronic hyperplastic candidiasis was also considered because of the clinical appearance of the oral lesion and systemic immunosuppression. The principal etiologic agent of this disease is the oral fungal pathogen Candida albicans. This pathogen manifests as white, well-demarcated, palpable, raised lesions that vary from small translucent whitish areas to large opaque plaques that cannot be scraped off. The lesions are symptomless and regress after appropriate antifungal therapy.8 The histopathological findings do not support this diagnosis.

 

Renal disease is a frequent manifestation of systemic amyloidosis and a leading cause of morbidity.9 Progressive loss of kidney function could lead to the development of chronic renal insufficiency, and this can result in uremia. Uremic stomatitis is a common intraoral clinical finding in cases of end-stage renal disease. It is characterized by the presence of plaques and crusts distributed on the buccal mucosa or on the dorsal or ventral surface of the tongue, gingiva, lips, and floor of the mouth.10 The patient in the present study presented with renal amyloidosis due to deposition of lambda light chains; however, the biochemical profile did not show renal failure. Therefore, we ruled out a diagnosis of uremic stomatitis.

 

A definitive diagnosis of OHL is established when the presence of EBV is demonstrated via histological analysis.11 Other nonspecific histopathological findings could include filiform hyperkeratosis and acanthosis with a vacuolar alteration of epithelial cells.12 In the present case, the patient was submitted to biopsy, and this revealed papillomatosis, hyperkeratosis, acanthosis, and ballooning degeneration in the stratum spinosum. The vacuolar alteration of prickle cells is an important characteristic of this condition.3 EBV can be detected by immunohistochemistry, in situ hybridization, and PCR. However, in situ hybridization is the most accurate and is considered as the gold standard technique in OHL diagnosis.13

 

OHL is a disease of the oral mucosa and is associated with EBV infection. The precise pathophysiological mechanism by which EBV infection causes OHL appears complex and is unknown. EBV is lymphocytotrophic as well as epitheliotropic and can be transmitted through the saliva.3 Several factors, including repeated direct infection of the tongueÕs superficial epithelial cells by EBV originating from saliva, productive EBV replication, EBV genetic evolution, and expression of specific EBV ŅlatentÓ genes, converge to result in the development of OHL.12

 

OHL was first described more than 20 years ago in individuals with HIV infection.14 However, OHL findings can also be associated with other conditions involving immunosuppression such as organ or bone marrow transplantation, chemotherapy, hematological malignancies, and the use of systemic steroids.3,12,14-16 Immunosuppressive drugs may also enable clonal expansion of EBV-infected B cells.17 In the present report, the patient underwent therapy with prednisone, methotrexate, dexamethasone, and cyclophosphamide which may explain the appearance of the lesion. These drugs have been associated with side effects on the immune system by decreasing the immunological response to various diseases and conditions.14

 

OHL is frequently asymptomatic, and it does not require treatment in such instances.18 Conversely, extensive OHL that involves taste perturbation could require treatment. This therapy could be oral or topical and includes the use of drugs that inhibit EBV replication. Acyclovir and valacyclovir have caused OHL regression in many patients.19 Topical treatment is commonly recommended because it has a low cost, is easy to use, has few side effects and is effective for a long period of time.3 In the present study, the patient received prophylactic acyclovir before autologous stem cell transplantation. The use of the prophylactic acyclovir and the suspension of immunosuppressant drug use after the transplant were probably responsible for OHL remission.

 

Conclusion

This is an unusual clinical presentation of OHL in individuals without HIV infection and systemic primary amyloidosis. Others conditions involving immune-suppression such as chemotherapy and the use of systemic steroids may decreasing the immunological response and enable clonal expansion of EBV-infected that has been associated with OHL. 

 

Acknowledgement

We would like to thank National Council for Scientific and Technological Development (CNPq) for their financial help.

 

Author Affiliations

1.Dr.Jeane de F‡tima Correia-Silva, 2.Dr.Renata Gon¨alves Resende, Department of Oral Pathology, Faculty of Dentistry, 3.Dr.Fernanda Maia Lodi, Stem Cell Transplant Unit, Hospital das Cl’nicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, 4.Dr.Brendan Conn, Department of Pathology, Royal Infirmary of Edinburgh, Edinburgh, Scotland, 5.Dr.Ricardo Alves Mesquita, 6.Dr.Ricardo Santiago Gomez, Department of Oral Pathology, Faculty of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

 

References

1.     Bhat A, Selmi C, Naguwa SM, Cheema GS, Gershwin ME. Currents concepts on the immunopathology of amyloidosis. Clin Rev Allergy Immunol. 2010;38(2-3):97-106.

2.     Fahrner KS, Black CC, Gosselin BJ. Localized amyloidosis of the tongue: a review. Am J Otolaryngol. 2004;25(3):186-9.

3.     Cho HH, Kim SH, Seo SH, Jung DS, Ko HC, Kim MB, et al. Oral hairy leukoplakia which occurred as a presenting sign of acute myeloid leukemia in a child. Ann Dermatol. 2010;22(1):73-6.

4.     Moura MD, Grossmann Sde M, Fonseca LM, Senna MI, Mesquita RA. Risk factors for oral hairy leukoplakia in HIV-infected adults of Brazil. J Oral Pathol Med. 2006;35(6):321-6.

5.     Moura MD, Guimaraes TR, Fonseca LM, de Almeida Pordeus I, Mesquita RA. A random clinical trial study to assess the efficiency of topical applications of podophyllin resin (25%) versus podophyllin resin (25%) together with acyclovir cream (5%) in the treatment of oral hairy leukoplakia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(1):64-71.

6.     van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; present concepts of management. Oral Oncol. 2010;46(6):423-5.

7.     Sapna N, Vandana KL. Idiopathic linear leukoplakia of gingiva: A rare case report. J Indian Soc Periodontol. 2010;14(3):198-200.

8.     Pankhurst CL. Candidiasis (oropharyngeal). Clin Evid (Online). 2012;20.

9.     Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, Hawkins PN. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356(23):2361-71.

10.  Antoniades DZ, Markopoulos AK, Andreadis D, Balaskas I, Patrikalou E, Grekas D. Ulcerative uremic stomatitis associated with untreated chronic renal failure: report of a case and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101(5):608-13.

11.  Braz-Silva PH, de Rezende NP, Ortega KL, de Macedo Santos RT, de Magalhaes MH. Detection of the Epstein-Barr virus (EBV) by in situ hybridization as definitive diagnosis of hairy leukoplakia. Head Neck Pathol. 2008;2(1):19-24.

12.  Gordins P, Sloan P, Spickett GP, Staines KS. Oral hairy leukoplakia in a patient on long-term anticonvulsant treatment with lamotrigine. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;111(5):17-23.

13.  Mabruk MJ, Flint SR, Toner M, Balluz I, Coleman D, Sullivan D, Atkins GJ. In situ hybridization and the polymerase chain reaction (PCR) in the analysis of biopsies and exfoliative cytology specimens for definitive diagnosis of oral hairy leukoplakia (OHL). J Oral Pathol Med. 1994;23(7):302-8.

14.  Kreuter A, Wieland U. Oral hairy leukoplakia: a clinical indicator of immunosuppression. CMAJ. 2011;183(8):93-2.

15.  Blomgren J, Back H. Oral hairy leukoplakia in a patient with multiple myeloma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82(4):408-10.

16.  Epstein JB, Sherlock CH, Wolber RA. Hairy leukoplakia after bone marrow transplantation. Oral Surg Oral Med Oral Pathol. 1993;75(6):690-5.

17.  Maurmann S, Fricke L, Wagner HJ, Schlenke P, Hennig H, Steinhoff J, Jabs WJ. Molecular parameters for precise diagnosis of asymptomatic Epstein-Barr virus reactivation in healthy carriers. J Clin Microbiol.  2003;41(12):541928.

18.  Nokta M. Oral manifestations associated with HIV infection. Curr HIV/AIDS Rep. 2008;5(1):5-12.

19.  Walling DM, Flaitz CM, Nichols CM. Epstein-Barr virus replication in oral hairy leukoplakia: response, persistence, and resistance to treatment with valacyclovir. J Infect Dis. 2003;188(6):883-90.

 

Corresponding Author

Dr.Jeane de F‡tima Correia-Silva,

Universidade Federal de Minas Gerais,

Faculdade de Odontologia, sala 3205

Av. Ant™nio Carlos 6627, Pampulha,

CEP 31270-901,

Belo Horizonte, Minas Gerais, Brazil

Email: jeanecorreia@gmail.com

Voice: +55 31 34092477,

Fax: +55 31 34092472

 

 


 

 

 

Source of Support: Nil, Conflict of Interest: None Declared.