- Email: [email protected]
Lipoid Proteinosis of the Oral Mucosa: Case Report and Review of the Literature
PATHOLOGY
RESEARCH AND PRAGICE
© Gustav Fischer Verlag
Lipoid Proteinosis of the Oral Mucosa: Case Report and Review of the Literature Kiriaki Aroni, Andreas Ch. Lazaris, Konstandina Papadimitriou, Helen Paraskevakou and Panayiotis S. Davaris Department of Pathology, Medical Faculty of Athens University, Greece
Summary
Concise Review of the Literature
We describe a 37-year-old woman who presented with progressive mouth dryness. Physical examination revealed long-standing plaques on the face and upper limbs, papular lesions of the oral cavity and tongue firmness. A lower lip biopsy was performed. Light microscopy demonstrated accumulation of PAS-positive material around blood vessels, capillaries and salivary gland canaliculi as well as focally massive hyaline deposits in the submucosa. Immunohistochemistry revealed widespread presence of type IV collagen in the hyaline material and around thickened blood vessels. Laminin immunoreactivity was particularly strong at thickened basement membranes. The above findings were compatible with lipoid proteinosis, which is likely to involve primary perturbation of collagen metabolism and production of glycoproteins.
Since 1929, when LP was established as a distinct clinical and histological entity by the dermatologist Urbach and the otolaryngologist Wiethe, approximately 300 cases have been reported; however, LP is not as rare as it appears from the literature, for its clinical and histological findings can be easily misinterpreted. The disease affects both sexes equally; its incidence is increased in Sweden and South Africa, and the age of the patients at diagnosis ranges from 6 months to over 60 years. Although an autosomal recessive mode of inheritance has been demonstrated in many cases of LP by parental consanguinity {l4], LP has been observed in two generations in some cases; therefore, heterozygotic LP manifestations are worth being investigated. LP is rarely reported to coexist with other genetic disorders (i.e. Ehlers-Danlos syndrome) [9]. LP mainly involves infiltration of the skin and mucous membranes. The patients' husky voice and thickened eyelids ("moniliform blepharosis") are particularly useful and early clues for the diagnosis of LP. Later, discrete or confluent yellowish, ivory or waxy nodules from pinhead to matchhead in size occur on the face, neck, axillae and hands in early life. Involvement of the scalp usually leads to loss of hair. Mucosal signs are present at birth or appear within the first few years of life. A gingival component of the LP entity has been confirmed [8]. Generally, the mouth is the most extensively affected area. Induration of the oral mucosa may also progressively begin in childhood [3]. Almost all
Key words: Lipoid proteinosis - Oral mucosa - Histology - Differential diagnosis
Introduction Lipoid proteinosis (LP) or hyalinosis cutis et mucosae is a rare genodermatosis characterized by deposits of hyaline material predominantly involving the skin and mucous membranes of the mouth and upper respiratory tract. In the present article, we discuss this condition with particular reference to recent data concerning its clinicopathological features, pathogenesis and differential diagnosis. To the best of our knowledge, the present case is the first one officially reported in the Greek population. Pathol. Res. Pract. 194: 855-859 (1998)
Address for correspondence: Prof. Panayiotis S. Davaris, Dept. of Pathology, Medical Faculty of Athens University, 75 Mikras Assias str., Goudi, GR - 11527 Athens, Greece. Tel.: 00301-7771206, Fax: 00301-7781487, E-mail: [email protected] 0344-0338/98/0194-0855$5.00/0
856 . K. Aroni et al.
oral tissues become infiltrated with white, elevated, pea-sized plaques that appear most frequently before puberty and gradually increase in severity. The tongue becomes woody and bound to the floor of the mouth. The dorsum loses its papillae. Firm, yellowish-white infiltrates soon develop in the lips. Inability to cry at birth, in the majority of cases, testifies to early laryngeal involvement. Laryngeal changes resulting in a hoarse cry may be the typical presenting sign of this disease at birth or early infancy [2]. These lesions can be estimated by computed tomography [II}. Even though there is no causal therapy, removal of nodular deposits on the vocal cords by laser surgery proves to be an effective treatment for hoarseness that many patients complain about. Nevertheless, depending on the activity of the disease, new deposits will probably develop. Patients may rarely require tracheostomy if severe laryngeal and pharyngeal narrowing impede ventilation. Infantile systemic hyalinosis is a fatal condition in which the symptoms appear soon after birth, and death often occurs before two years of age. Nevertheless, LP generally pursues a benign and chronic course, although it causes functional and cosmetic problems. Severe visceral involvement may occur in LP, even in previously undiagnosed patients with mild cutaneous manifestations of the disease [1]. The systemic nature of LP has been elucidated by examination of fibroblasts in both affected and uninvolved skin of patients with LP, showing a reduced ratio of type I to type III procollagen mRNA levels, and by autopsy studies revealing that LP may involve any organ of the body. However, symptoms referable to systemic organ involvement are usually not reported. A "bean-shaped" intracranial calcification has been described above the pituitary fossa in at least 70% of cases and may be seen in persons older than 10 years of age. It is pathognomonic and may lead to the onset of convulsive seizures. The characteristic histological findings in both the skin and mucosa include extensive deposits of amorphous eosinophilic material in the papillary dermis along capillaries and sweat glands. There is strong evidence that alteration in the distribution pattern of a genetically distinct collagen type may be responsible for the deposition of hyaline-like material. Evidence of clinical findings in combination with laboratory findings establishes the diagnosis of LP. Apart from dermabrasion, chemical skin peeling and blepharoplasty, until recently, no effective treatment has been known.
Report of a Case A 37-year-old Greek woman with no previously diagnosed genetic disorder was referred for management of mild progressive xerostomia, which had started two years
earlier. Few cutaneous lesions had developed during the last decade, presenting as waxy papules and plaques on the face, dorsal aspects of the hands and fingers. No skin biopsy had been taken. The vocal cords and the epiglottis were relatively thickened by focal infiltration of grayish material. However, the patient had suffered neither from hoarseness nor from any other symptom of visceral involvement; blood counts, serum analysis, serum lipids and cholesterol, immunoelectrophoresis, quantitative immunoglobulins and the erythrocyte sedimentation rate were normal. No kind of autoantibody was found. Examination of the oral cavity showed some white, focally yellowish, rough micropapular patches on the inner surfaces of the lips, the under surface of the tongue, the fauces and the uvula. The oral mucosa felt thick on palpation and its appearance was flabby and inflamed. The frenulum of the tongue was indurated and shortened by the protruding yellowish infiltrates. As a consequence, the patient could not protrude her tongue. Despite the fact that the tongue retained a normal size and surface, it was movable only with difficulty. In the areas of the sublingual glands, bulging ivory-colored depositions were seen. A mild gross gingival enlargement was also observed. A lower lip biopsy measuring 0.8xO.7xOA cm and exhibiting white papular deposits was sent for histological examination. The patient is being treated with oral dimethyl sulphoxide at an initial dosage of 40 mglkg/day. This dipolar aprotic substance is claimed to have the ability to dissolve collagen and scavenge hydroxyl radicals; its reported actions also include membrane penetration and anti-inflammatory effects. Nevertheless, its long term clinical utility remains controversial [I2}.
Material and Methods The lip biopsy was fixed in 10% neutrally buffered formaldehyde solution, and numerous blocks were embedded in paraffin. Before fixation, some frozen sections had been taken. Paraffin sections were stained with hematoxylin-eosin, periodic acid-Schiff (PAS) with and without diastase digestion, Verhoeff-van Gieson stain for elastic fibers, Congo red for amyloid substance and alcian blue stain at a pH of 1.0 and 2.9 for sulphated and non-sulphated acidic mucopolysaccharides, respectively. Sudan black B stain for neutral fat was performed on cryostat sections. Paraffin sections were also immunostained for collagen type IV (Dako, Glostrup, Denmark, mouse monoclonal antibody clone CIV 22) and laminin (Dako, Glostrup, Denmark, rabbit antibody) employing the labeled avidin-biotin method.
Pathologic Findings In hematoxylin and eosin-stained sections, the patches were produced by subepithelial confluent deposits of
Lipoid Proteinosis of the Oral Mucosa . 857
Fig. 1. Deposits of hyalin substance occupy the submucosa and blood vessel walls (arrows) (Hematoxylineosin, original magnification x200).
Fig. 2. Intense collagen IV immunoreactivity of thickened subepithelial capillaries (arrows) (ABC complex/ HRP, original magnification x400).
an extracellular, amorphous, pink and hyaline substance in the submucosa. In detail, the hyaline deposits consisted of masses of weakly acidophilic and rather acellular material, frequently forming concentric mantles around submucosal vessels which remained patent (Fig. I) and occasionally contained small thrombi in their lumen. In general, blood vessel walls were homogeneously thickened, while thickened hyaline membranes were seen around atrophic minor salivary glands with a moderate pericanalicular fibrosis. Only a few fibroblasts were present in the amorphous band, but, in the deeper layers, collagen bundles of varying size surrounded by hyaline matrix were associated with more frequent, slender fibroblasts. Focal mononuclear in-
flamrnatory cell infiltration was also evident. The stratified squamous epithelium was of variable thickness and possessed elongated rete-processes. Histochemically, the hyaline material stained strongly with PAS with and without diastase digestion. Thus, the deposits could be clearly detected around thickened vessels, capillaries and salivary gland canaliculi. The finding that the hyaline material was largely diastaseresistant indicates the presence of glycoproteins and/or proteoglycan complexes. The deposits were strongly suggestive of LP, and were also slightly stained with alcian blue at a pH of 2.9, but were negative for alcian blue at a pH of 1.0, Congo red or elastic fibers. A few droplets of neutral fat were barely distinguishable with
858 . K. Aroni et al.
Sudan stain; actually, the presence of lipid in LP is known to be generally variable. The accumulation of lipids in LP is a late and presumably secondary phenomenon and is likely to result from adherence of lipids to glycoproteins rather than from abnormal lipid production. Strong binding of the antibody to type IV collagen was detected throughout the hyaline deposits as well as around thickened blood vessels of the oral mucosa (Fig. 2). Laminin immunolabeling was particularly intense at thickened basement membranes.
Discussion In the present study, immunohistochemistry confirmed the altered composition of the oral mucosa's extracellular matrix in LP, as previously described [15]. As judged by the contents of glycine and hydroxyprolin, normal skin contains about 80% collagen, but skin involved in cases of LP contains only 20% collagen as a result of a large accumulation of overproduced non-collagenous glycoproteins [6J. The deposited material probably consists of matrix glycoproteins with increased laminin and collagen of types IV and V, and a relative decrease in collagen types I and III. In detail, types IV and V collagen are increased around vessels and types I and III collagen are reduced in quantity and abnormally hydrolyzed in the dermis. A complex relationship between type IV and type III-like collagen components has been postulated [10]. In any case, the total collagen content of LP is found to be significantly reduced, indicating a fault either in the biosynthesis of collagen or excess of degradation. In general, LP seems to be a consequence of a specific overproduction of basement membrane type IV collagen [13J by epithelial or endothelial cells and increased synthesis of extracellular non-collagenous glycoproteins by fibroblasts. The name "lipoid" is used because the hyaline material may also have a lipoid component which, however, could not be easily identified in the examined tissue specimen of the present case. The lipid accumulation has been attributed to the adherence of lipids to glycoproteins rather than to a primary lipoid metabolic effect. Therefore, lipids are not an essential feature of the disease, whether they are free or loosely bound to the hyaline. Actually, the evolution of LP appears to follow two stages: firstly, basement membrane components accumulate at the normal site of vascular, muscular and epithelial basement membranes; later on, lipids and amorphous material fill the superficial dermis, pushing apart the normal collagen bundles. Ultrastructurally, the massive hyaline material is composed of a mixture of an amorphous, granular, electron-dense matrix with no distincitve periodicity and illdefined, wavy and stringy rare fine filaments inter-
spersed with frayed collagen fibers. The characteristic aspect of multiplication immediately surrounding the basal laminae of blood vessel walls compressing the endothelial cells in an "onion skin" arrangement is of particular diagnostic importance. Thus, two different substances in lesions of LP become evident on electron microscopy. One substance is true hyalin, produced by fibroblasts, and the other represents hyalin-like material consisting of multiplications of basal laminae and is produced by various cells, but not by fibroblasts [6]. Amyloidosis is probably the main differential diagnosis. The hyaline deposits of LP are negative or only weakly positive for amyloid stains. In contrast to amyloid, deposits of LP usually, but not always, show a positive reaction for neutral lipid and stain with alcian blue at a pH of 2.9. Our study confirms that the hyaline material is also immunoreactive for collagen type IV and laminin. In contrast to the characteristic straight nonbranching fibrils of amyloid, electron microscopy reveals amorphous granular material around blood vessels in LP. It has been reported that LP may cause xerostomia [5 J as evidenced in our patient. In addition, patients suffering from LP may exhibit a non-specific inflammation in the salivary glands. So, Sjogren's syndrome and sialadenitis should be ruled out. In the first few years of life, gingival overgrowth can be seen in several inherited conditions; a few cases can actually demonstrate features of both systemic hyalinosis and juvenile hyaline fibromatosis. The latter is also an autosomal recessive condition with similar histological changes but, in most cases, is not lethal like the former disease [4]. It is suggested that systemic hyalinosis should be preceded by "infantile" or "juvenile," depending on the clinical presentation [7 J. In the skin, hyaline deposits similar to those of LP can be produced by the different types of porphyria [11], but these diseases do not involve the lower dermis and are usually limited to sun-exposed areas of the skin. The progressive hyalinization of sweat glands in LP is a striking and constant difference. In porphyria, involvement of the membrana propria of the sweat glands is rare and the deposits are more limited in distribution, only being perivascular. Furthermore, in erythropoietic protoporphyria, the hyaline material does not encroach upon the adjacent dermis as much as the hyaline material does in LP and tends to stain less intensely with Hale's colloidal iron method than in LP.
References 1. Caccamo D, Jaen A, Telenta M, Varela E, Tiscornia 0 (1994) Lipoid proteinosis of the small bowel. Arch Pathol Lab Med 118: 572-574
Lipoid Proteinosis of the Oral Mucosa . 859 2. Chaudhary SJ, Dayal PK (1995) Hyalinosis cutis et mucosae. Review with a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 80: 168-171 3. Cinaz P, Guvenir T, Gonlusen G (1993) Lipoid proteinosis: Urbach-Wiethe disease. Acta Paediatr 82: 892-893 4. Devlin H, Sloan P, Thakkar NS (1995) Oral manifestations of infantile systemic hyalinosis. J Oral Pathol Med 24: 140-143 5. Disdier P, Harle JR, Andrac L, Swiader L, Weiller PJ (1994) Specific xerostomia during Urbach-Wiethe disease. Dermatology 188: 50-51 6. Elder D, ed. (1997) Lever's Histopathology of the Skin. Eighth Edition, pp 375-376. Lippincott-Raven, Philadelphia 7. Hutchinson I (1996) Juvenile systemic hyalinosis - a rare cause of gingival hypertrophy: a case report. Int J Paediatr Dent 6: 39-43 8. Israel H (1992) Gingival lesions in lipoid proteinosis. J PeriodontoI63:561-564 9. Konig I, Hausser I, Anton-Lamprecht I, Schroter R, Petzoldt D (1994) Hyalinosis cutis et mucosae and EhlersDanlos syndrome. A rare combination of syndromes. Hautarzt 45: 108-112
10. Muda AO, Paradisi M, Angelo C, Mostaccioli S, Atzori F, Puddu P, Faraggiana T (1995) Lipoid proteinosis: clinical, histologic, and ultrastructural investigations. Cutis 56:220-224 11. Ozbek SS, Akyar S, Turgay M (1994) Case report: computed tomography findings in lipoid proteinosis: report of two cases. Br J Radiol 67: 207-209 12. Ozkaya-Bayazit E, Ozarmagan G, Baykal C, Ulug T (1997) Oral DMSO therapy in 3 patients with lipoid proteinosis. Results of long-term therapy. Hautarzt 48: 477-481 13. Paller AS (1994) Histology of lipoid proteinosis. Questions and answers. JAMA 272: 564-565 14. Rizzo R, Ruggieri M, Micali G, Tine A, Sanfilippo S, Pavone L (1997) Lipoid proteinosis: a case report. Pediatr Dermatol14: 22-25 15. Tranchina MG, Scarpulla G (1995) Lipoid proteinosis. Pathologica 87: 709-711
Received: April 14, 1998 Accepted in revised version: September 3, 1998
RESEARCH AND PRAGICE
© Gustav Fischer Verlag
Lipoid Proteinosis of the Oral Mucosa: Case Report and Review of the Literature Kiriaki Aroni, Andreas Ch. Lazaris, Konstandina Papadimitriou, Helen Paraskevakou and Panayiotis S. Davaris Department of Pathology, Medical Faculty of Athens University, Greece
Summary
Concise Review of the Literature
We describe a 37-year-old woman who presented with progressive mouth dryness. Physical examination revealed long-standing plaques on the face and upper limbs, papular lesions of the oral cavity and tongue firmness. A lower lip biopsy was performed. Light microscopy demonstrated accumulation of PAS-positive material around blood vessels, capillaries and salivary gland canaliculi as well as focally massive hyaline deposits in the submucosa. Immunohistochemistry revealed widespread presence of type IV collagen in the hyaline material and around thickened blood vessels. Laminin immunoreactivity was particularly strong at thickened basement membranes. The above findings were compatible with lipoid proteinosis, which is likely to involve primary perturbation of collagen metabolism and production of glycoproteins.
Since 1929, when LP was established as a distinct clinical and histological entity by the dermatologist Urbach and the otolaryngologist Wiethe, approximately 300 cases have been reported; however, LP is not as rare as it appears from the literature, for its clinical and histological findings can be easily misinterpreted. The disease affects both sexes equally; its incidence is increased in Sweden and South Africa, and the age of the patients at diagnosis ranges from 6 months to over 60 years. Although an autosomal recessive mode of inheritance has been demonstrated in many cases of LP by parental consanguinity {l4], LP has been observed in two generations in some cases; therefore, heterozygotic LP manifestations are worth being investigated. LP is rarely reported to coexist with other genetic disorders (i.e. Ehlers-Danlos syndrome) [9]. LP mainly involves infiltration of the skin and mucous membranes. The patients' husky voice and thickened eyelids ("moniliform blepharosis") are particularly useful and early clues for the diagnosis of LP. Later, discrete or confluent yellowish, ivory or waxy nodules from pinhead to matchhead in size occur on the face, neck, axillae and hands in early life. Involvement of the scalp usually leads to loss of hair. Mucosal signs are present at birth or appear within the first few years of life. A gingival component of the LP entity has been confirmed [8]. Generally, the mouth is the most extensively affected area. Induration of the oral mucosa may also progressively begin in childhood [3]. Almost all
Key words: Lipoid proteinosis - Oral mucosa - Histology - Differential diagnosis
Introduction Lipoid proteinosis (LP) or hyalinosis cutis et mucosae is a rare genodermatosis characterized by deposits of hyaline material predominantly involving the skin and mucous membranes of the mouth and upper respiratory tract. In the present article, we discuss this condition with particular reference to recent data concerning its clinicopathological features, pathogenesis and differential diagnosis. To the best of our knowledge, the present case is the first one officially reported in the Greek population. Pathol. Res. Pract. 194: 855-859 (1998)
Address for correspondence: Prof. Panayiotis S. Davaris, Dept. of Pathology, Medical Faculty of Athens University, 75 Mikras Assias str., Goudi, GR - 11527 Athens, Greece. Tel.: 00301-7771206, Fax: 00301-7781487, E-mail: [email protected] 0344-0338/98/0194-0855$5.00/0
856 . K. Aroni et al.
oral tissues become infiltrated with white, elevated, pea-sized plaques that appear most frequently before puberty and gradually increase in severity. The tongue becomes woody and bound to the floor of the mouth. The dorsum loses its papillae. Firm, yellowish-white infiltrates soon develop in the lips. Inability to cry at birth, in the majority of cases, testifies to early laryngeal involvement. Laryngeal changes resulting in a hoarse cry may be the typical presenting sign of this disease at birth or early infancy [2]. These lesions can be estimated by computed tomography [II}. Even though there is no causal therapy, removal of nodular deposits on the vocal cords by laser surgery proves to be an effective treatment for hoarseness that many patients complain about. Nevertheless, depending on the activity of the disease, new deposits will probably develop. Patients may rarely require tracheostomy if severe laryngeal and pharyngeal narrowing impede ventilation. Infantile systemic hyalinosis is a fatal condition in which the symptoms appear soon after birth, and death often occurs before two years of age. Nevertheless, LP generally pursues a benign and chronic course, although it causes functional and cosmetic problems. Severe visceral involvement may occur in LP, even in previously undiagnosed patients with mild cutaneous manifestations of the disease [1]. The systemic nature of LP has been elucidated by examination of fibroblasts in both affected and uninvolved skin of patients with LP, showing a reduced ratio of type I to type III procollagen mRNA levels, and by autopsy studies revealing that LP may involve any organ of the body. However, symptoms referable to systemic organ involvement are usually not reported. A "bean-shaped" intracranial calcification has been described above the pituitary fossa in at least 70% of cases and may be seen in persons older than 10 years of age. It is pathognomonic and may lead to the onset of convulsive seizures. The characteristic histological findings in both the skin and mucosa include extensive deposits of amorphous eosinophilic material in the papillary dermis along capillaries and sweat glands. There is strong evidence that alteration in the distribution pattern of a genetically distinct collagen type may be responsible for the deposition of hyaline-like material. Evidence of clinical findings in combination with laboratory findings establishes the diagnosis of LP. Apart from dermabrasion, chemical skin peeling and blepharoplasty, until recently, no effective treatment has been known.
Report of a Case A 37-year-old Greek woman with no previously diagnosed genetic disorder was referred for management of mild progressive xerostomia, which had started two years
earlier. Few cutaneous lesions had developed during the last decade, presenting as waxy papules and plaques on the face, dorsal aspects of the hands and fingers. No skin biopsy had been taken. The vocal cords and the epiglottis were relatively thickened by focal infiltration of grayish material. However, the patient had suffered neither from hoarseness nor from any other symptom of visceral involvement; blood counts, serum analysis, serum lipids and cholesterol, immunoelectrophoresis, quantitative immunoglobulins and the erythrocyte sedimentation rate were normal. No kind of autoantibody was found. Examination of the oral cavity showed some white, focally yellowish, rough micropapular patches on the inner surfaces of the lips, the under surface of the tongue, the fauces and the uvula. The oral mucosa felt thick on palpation and its appearance was flabby and inflamed. The frenulum of the tongue was indurated and shortened by the protruding yellowish infiltrates. As a consequence, the patient could not protrude her tongue. Despite the fact that the tongue retained a normal size and surface, it was movable only with difficulty. In the areas of the sublingual glands, bulging ivory-colored depositions were seen. A mild gross gingival enlargement was also observed. A lower lip biopsy measuring 0.8xO.7xOA cm and exhibiting white papular deposits was sent for histological examination. The patient is being treated with oral dimethyl sulphoxide at an initial dosage of 40 mglkg/day. This dipolar aprotic substance is claimed to have the ability to dissolve collagen and scavenge hydroxyl radicals; its reported actions also include membrane penetration and anti-inflammatory effects. Nevertheless, its long term clinical utility remains controversial [I2}.
Material and Methods The lip biopsy was fixed in 10% neutrally buffered formaldehyde solution, and numerous blocks were embedded in paraffin. Before fixation, some frozen sections had been taken. Paraffin sections were stained with hematoxylin-eosin, periodic acid-Schiff (PAS) with and without diastase digestion, Verhoeff-van Gieson stain for elastic fibers, Congo red for amyloid substance and alcian blue stain at a pH of 1.0 and 2.9 for sulphated and non-sulphated acidic mucopolysaccharides, respectively. Sudan black B stain for neutral fat was performed on cryostat sections. Paraffin sections were also immunostained for collagen type IV (Dako, Glostrup, Denmark, mouse monoclonal antibody clone CIV 22) and laminin (Dako, Glostrup, Denmark, rabbit antibody) employing the labeled avidin-biotin method.
Pathologic Findings In hematoxylin and eosin-stained sections, the patches were produced by subepithelial confluent deposits of
Lipoid Proteinosis of the Oral Mucosa . 857
Fig. 1. Deposits of hyalin substance occupy the submucosa and blood vessel walls (arrows) (Hematoxylineosin, original magnification x200).
Fig. 2. Intense collagen IV immunoreactivity of thickened subepithelial capillaries (arrows) (ABC complex/ HRP, original magnification x400).
an extracellular, amorphous, pink and hyaline substance in the submucosa. In detail, the hyaline deposits consisted of masses of weakly acidophilic and rather acellular material, frequently forming concentric mantles around submucosal vessels which remained patent (Fig. I) and occasionally contained small thrombi in their lumen. In general, blood vessel walls were homogeneously thickened, while thickened hyaline membranes were seen around atrophic minor salivary glands with a moderate pericanalicular fibrosis. Only a few fibroblasts were present in the amorphous band, but, in the deeper layers, collagen bundles of varying size surrounded by hyaline matrix were associated with more frequent, slender fibroblasts. Focal mononuclear in-
flamrnatory cell infiltration was also evident. The stratified squamous epithelium was of variable thickness and possessed elongated rete-processes. Histochemically, the hyaline material stained strongly with PAS with and without diastase digestion. Thus, the deposits could be clearly detected around thickened vessels, capillaries and salivary gland canaliculi. The finding that the hyaline material was largely diastaseresistant indicates the presence of glycoproteins and/or proteoglycan complexes. The deposits were strongly suggestive of LP, and were also slightly stained with alcian blue at a pH of 2.9, but were negative for alcian blue at a pH of 1.0, Congo red or elastic fibers. A few droplets of neutral fat were barely distinguishable with
858 . K. Aroni et al.
Sudan stain; actually, the presence of lipid in LP is known to be generally variable. The accumulation of lipids in LP is a late and presumably secondary phenomenon and is likely to result from adherence of lipids to glycoproteins rather than from abnormal lipid production. Strong binding of the antibody to type IV collagen was detected throughout the hyaline deposits as well as around thickened blood vessels of the oral mucosa (Fig. 2). Laminin immunolabeling was particularly intense at thickened basement membranes.
Discussion In the present study, immunohistochemistry confirmed the altered composition of the oral mucosa's extracellular matrix in LP, as previously described [15]. As judged by the contents of glycine and hydroxyprolin, normal skin contains about 80% collagen, but skin involved in cases of LP contains only 20% collagen as a result of a large accumulation of overproduced non-collagenous glycoproteins [6J. The deposited material probably consists of matrix glycoproteins with increased laminin and collagen of types IV and V, and a relative decrease in collagen types I and III. In detail, types IV and V collagen are increased around vessels and types I and III collagen are reduced in quantity and abnormally hydrolyzed in the dermis. A complex relationship between type IV and type III-like collagen components has been postulated [10]. In any case, the total collagen content of LP is found to be significantly reduced, indicating a fault either in the biosynthesis of collagen or excess of degradation. In general, LP seems to be a consequence of a specific overproduction of basement membrane type IV collagen [13J by epithelial or endothelial cells and increased synthesis of extracellular non-collagenous glycoproteins by fibroblasts. The name "lipoid" is used because the hyaline material may also have a lipoid component which, however, could not be easily identified in the examined tissue specimen of the present case. The lipid accumulation has been attributed to the adherence of lipids to glycoproteins rather than to a primary lipoid metabolic effect. Therefore, lipids are not an essential feature of the disease, whether they are free or loosely bound to the hyaline. Actually, the evolution of LP appears to follow two stages: firstly, basement membrane components accumulate at the normal site of vascular, muscular and epithelial basement membranes; later on, lipids and amorphous material fill the superficial dermis, pushing apart the normal collagen bundles. Ultrastructurally, the massive hyaline material is composed of a mixture of an amorphous, granular, electron-dense matrix with no distincitve periodicity and illdefined, wavy and stringy rare fine filaments inter-
spersed with frayed collagen fibers. The characteristic aspect of multiplication immediately surrounding the basal laminae of blood vessel walls compressing the endothelial cells in an "onion skin" arrangement is of particular diagnostic importance. Thus, two different substances in lesions of LP become evident on electron microscopy. One substance is true hyalin, produced by fibroblasts, and the other represents hyalin-like material consisting of multiplications of basal laminae and is produced by various cells, but not by fibroblasts [6]. Amyloidosis is probably the main differential diagnosis. The hyaline deposits of LP are negative or only weakly positive for amyloid stains. In contrast to amyloid, deposits of LP usually, but not always, show a positive reaction for neutral lipid and stain with alcian blue at a pH of 2.9. Our study confirms that the hyaline material is also immunoreactive for collagen type IV and laminin. In contrast to the characteristic straight nonbranching fibrils of amyloid, electron microscopy reveals amorphous granular material around blood vessels in LP. It has been reported that LP may cause xerostomia [5 J as evidenced in our patient. In addition, patients suffering from LP may exhibit a non-specific inflammation in the salivary glands. So, Sjogren's syndrome and sialadenitis should be ruled out. In the first few years of life, gingival overgrowth can be seen in several inherited conditions; a few cases can actually demonstrate features of both systemic hyalinosis and juvenile hyaline fibromatosis. The latter is also an autosomal recessive condition with similar histological changes but, in most cases, is not lethal like the former disease [4]. It is suggested that systemic hyalinosis should be preceded by "infantile" or "juvenile," depending on the clinical presentation [7 J. In the skin, hyaline deposits similar to those of LP can be produced by the different types of porphyria [11], but these diseases do not involve the lower dermis and are usually limited to sun-exposed areas of the skin. The progressive hyalinization of sweat glands in LP is a striking and constant difference. In porphyria, involvement of the membrana propria of the sweat glands is rare and the deposits are more limited in distribution, only being perivascular. Furthermore, in erythropoietic protoporphyria, the hyaline material does not encroach upon the adjacent dermis as much as the hyaline material does in LP and tends to stain less intensely with Hale's colloidal iron method than in LP.
References 1. Caccamo D, Jaen A, Telenta M, Varela E, Tiscornia 0 (1994) Lipoid proteinosis of the small bowel. Arch Pathol Lab Med 118: 572-574
Lipoid Proteinosis of the Oral Mucosa . 859 2. Chaudhary SJ, Dayal PK (1995) Hyalinosis cutis et mucosae. Review with a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 80: 168-171 3. Cinaz P, Guvenir T, Gonlusen G (1993) Lipoid proteinosis: Urbach-Wiethe disease. Acta Paediatr 82: 892-893 4. Devlin H, Sloan P, Thakkar NS (1995) Oral manifestations of infantile systemic hyalinosis. J Oral Pathol Med 24: 140-143 5. Disdier P, Harle JR, Andrac L, Swiader L, Weiller PJ (1994) Specific xerostomia during Urbach-Wiethe disease. Dermatology 188: 50-51 6. Elder D, ed. (1997) Lever's Histopathology of the Skin. Eighth Edition, pp 375-376. Lippincott-Raven, Philadelphia 7. Hutchinson I (1996) Juvenile systemic hyalinosis - a rare cause of gingival hypertrophy: a case report. Int J Paediatr Dent 6: 39-43 8. Israel H (1992) Gingival lesions in lipoid proteinosis. J PeriodontoI63:561-564 9. Konig I, Hausser I, Anton-Lamprecht I, Schroter R, Petzoldt D (1994) Hyalinosis cutis et mucosae and EhlersDanlos syndrome. A rare combination of syndromes. Hautarzt 45: 108-112
10. Muda AO, Paradisi M, Angelo C, Mostaccioli S, Atzori F, Puddu P, Faraggiana T (1995) Lipoid proteinosis: clinical, histologic, and ultrastructural investigations. Cutis 56:220-224 11. Ozbek SS, Akyar S, Turgay M (1994) Case report: computed tomography findings in lipoid proteinosis: report of two cases. Br J Radiol 67: 207-209 12. Ozkaya-Bayazit E, Ozarmagan G, Baykal C, Ulug T (1997) Oral DMSO therapy in 3 patients with lipoid proteinosis. Results of long-term therapy. Hautarzt 48: 477-481 13. Paller AS (1994) Histology of lipoid proteinosis. Questions and answers. JAMA 272: 564-565 14. Rizzo R, Ruggieri M, Micali G, Tine A, Sanfilippo S, Pavone L (1997) Lipoid proteinosis: a case report. Pediatr Dermatol14: 22-25 15. Tranchina MG, Scarpulla G (1995) Lipoid proteinosis. Pathologica 87: 709-711
Received: April 14, 1998 Accepted in revised version: September 3, 1998