- Email: [email protected]
Multiple Symmetric Lipomatosis: Case Report and Review of the Literature
1365
MENINGAUD, PITAK-ARNNOP, AND BERTRAND
J Oral Maxillofac Surg 65:1365-1369, 2007
Multiple Symmetric Lipomatosis: Case Report and Review of the Literature Jean-Paul Meningaud, MD, PhD, FEBOMS,* Poramate Pitak-Arnnop, DDS, Diploma(OMS),† and Jacques-Charles Bertrand, MD‡ Multiple symmetric lipomatosis (MSL) is a rare disease mainly characterized by large subcutaneous fatty masses distributed around the neck, shoulders, upper extremities, and upper dorsal regions. Sir Benjamin Brodie first described MSL in 1846,1 but Otto Madelung described the first case series in 1888 (35 cases).2 The following decade, Pierre Emile Launois and Raoul Bensaude presented a larger case series of 65 patients.3 Since then, approximately 200 cases have been published in the medical literature.4 MSL has been designated by several different names, including Madelung’s disease, Launois-Bensaude’s disease, symmetrical adenolipomatosis, benign symmetrical lipomatosis, lipoma diffusa symmetrica, and lipomatosis simplex indolens. The aims of this article are to report the sequential management of a 50-year-old French patient with MSL and to provide a comprehensive and thorough overview of the current concepts concerning this disease with an emphasis on understanding the etiologies and modalities of treatment.
Report of a Case The patient was a 50-year-old French man (height 1.69 m, weight 69 kg) with a history of alcohol abuse, heavy smoking, and 2 surgical procedures for vertebral disc herniation performed 2 and 4 years earlier. One of his uncles had MSL. The patient was referred to the maxillofacial surgery department with a 5-year history of massive, painless lipomas diffusely distributed over his neck, limiting head motion. On
Received from the Department of Maxillofacial Surgery, PitiéSalpêtrière Hospital, Paris, France. *Consultant, Maxillofacial Surgeon. †Surgical Fellow. ‡Professor and Head. Address correspondence and reprint requests to Dr Meningaud: Service de Chirurgie Maxillo-Faciale, CHU Pitié-Salpêtrière, 47 bd de l’hôpital, 75651 Paris, Cedex 13, France; e-mail: [email protected] © 2007 American Association of Oral and Maxillofacial Surgeons
0278-2391/07/6507-0018$32.00/0 doi:10.1016/j.joms.2005.10.045
palpation, the fat deposits had a soft consistency. A large posterior cervical lipoma formed a continuous mass with anterolateral deposits (Fig 1). In addition, he had several small lipomas located bilaterally in his shoulders. No cervical lymph nodes were palpable and the masses could not be transilluminated. There were no signs of dyspnea, dysphagia, or dysphonia. The remaining clinical examination and routine laboratory tests were unremarkable except for elevated gamma GT values. Computed tomography scan confirmed the presence of extensive masses with fat density in the referred area without mediastinal involvement (Fig 2). Considering the extent of disease, a 3-stage lipectomy with a 2-month interval was proposed to the patient. Lipectomies were performed via open cervical approaches; each operation removed one third of the total mass. Intraoperatively, the fat was nonencapsulated; it infiltrated normal subcutaneous fat and was intertwined with carotid arteries and jugular veins. The weights of the excised specimens were 280, 430, and 300 g. Histologic studies were consistent with the clinical diagnosis. They showed a proliferation of large, empty-appearing cells with compressed nuclei, typical of adipocytes with a slight increase of connective tissue. There was no cellular atypia or areas of necrosis. They exhibited large adult fat cells within a normal amount of intercellular connective tissue. No abnormal intracellular constituents were identified. Three hours after the first lipectomy, the postoperative course was marked by a large hematoma producing dyspnea; surgical evacuation was performed immediately. Instead of 1 vacuum drain for the first operation, 3 vacuum drains were used for the second and third operations. Otherwise, outcomes were unremarkable with a good functional and esthetic result (Fig 3). Abstinence from alcohol was strongly recommended but was refused by the patient. Nevertheless, no recurrence was noted at the 18-month follow-up visit.
Discussion and Overview of the Literature EPIDEMIOLOGY: A RARE DISEASE
Epidemiologically, the incidence of MSL is highest in males with a history of alcohol abuse.5 However, chronic alcoholism is considered as an important but not indispensable pathogenic factor.6 MSL was found in association with alcohol in 60% to 90% in different series. The male to female ratio has been reported to be as high as 15:1.5 Onset occurs predominantly in the third, fourth, and fifth decades of life,7 but cases
1366
MULTIPLE SYMMETRIC LIPOMATOSIS
FIGURE 1. A, Anterior, and B, right lateral preoperative photographs of a patient with MSL.
FIGURE 3. A, Anterior, and B, right lateral postoperative photographs of a patient with MSL.
Meningaud, Pitak-Arnnop, and Bertrand. Multiple Symmetric Lipomatosis. J Oral Maxillofac Surg 2007.
Meningaud, Pitak-Arnnop, and Bertrand. Multiple Symmetric Lipomatosis. J Oral Maxillofac Surg 2007.
of pediatric patients have been reported.8 The general incidence is unknown, but the prevalence may be higher in Mediterranean countries (notably in Italy, Spain, and France) where most of the reported cases come from including the present case. A DIAGNOSIS MAINLY ESTABLISHED BY PHYSICAL EXAMINATION
The patient’s appearance is usually characterized by the presence of symmetrical accumulation of multiple painless unencapsulated lipomas that frequently encircle vital anatomic structures, predominately in the neck and upper extremities. The patient can have more than 1,000 lipomas of various diameters ranging in size from 1 to 20 cm in different regions of the body. Donhauser et al9 distinguish 3 types of MSL: 1) horse collar lipoma, 2) pseudoathletic appearance, and 3) gynecoid type. Features of more than 1 type can be found in some patients. The patient reported here had horse collar lipoma. The Madelung’s collar is usually symmetrical, slowly progressive, and asymptomatic with the ex-
FIGURE 2. Computed tomography scan of the neck shows a continuous fatty mass formed by a large posterior cervical lipoma and anterolateral lipomas. Density measurements were consistent with fat tissue. Meningaud, Pitak-Arnnop, and Bertrand. Multiple Symmetric Lipomatosis. J Oral Maxillofac Surg 2007.
ception of difficulties in turning the head. However, cases of deep infiltration of mediastinal structures with compression of major vessels, nerves, trachea, mainstream bronchi and esophagus leading to dyspnea, dysphagia, and dysphonia have been reported. In addition, the larynx can be narrowed by direct compression, by fatty infiltration of the larynx itself,10,11 and by infiltration or compression of recurrent laryngeal nerves.12 Involvement of the tongue in the form of macroglossia has also been reported.13 Deposit of lipomatous tissue in the pharyngeal region is probably a factor favoring obstructive sleep apnea; thus, greater care should be taken in patients with horse collar lipoma and symptoms of daytime sleepiness.14 MSL may be associated with metabolic diseases in obese patients (impaired fasting glucose control, diabetes mellitus, hyperlipidemia, and so on), but the majority of patients with MSL are not obese. Patients with MSL frequently have a history of alcohol abuse, but there is no clear relation between lipomata growth and onset or end of alcohol consumption. However, the disease is often associated with the sequels of alcohol abuse (ie, hepatopathy,15 hyperuricemia, hyperlipidemia, macrocytic anemia, and oral cancer). The neuropathy has often been attributed to alcohol toxicity, but seems in reality to be a complication of the lipoma itself. The microscopic findings in many cases of MSL are progressive axonal atrophy, whereas the histologic hallmarks of alcoholic neuropathy are axonal degeneration and demyelination.16,17 Besides, such neuropathies can be observed in patients with MSL who are not alcohol addicts,18 and notably in children.8 The polyneuropathy described as sensory, motor, or autonomic dysfunction is noted in up to 85% of cases, 80% of which develop a physical disability. Polyneuropathy develops several years after onset of MSL. Under light microscopy, histology samples exhibit the morphology of simple lipoma (Fig 3). Adipocytes look like mature monovacuolar adipocytes of white fat surrounded by connective tissue of variable den-
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MENINGAUD, PITAK-ARNNOP, AND BERTRAND
sity. The only slight difference is that they are on average smaller than normal adipocytes from the same patient. Nevertheless, electron microscopy examination of adipocyte and cultured preadipocyte ultrastructures reveals features of brown fat (more details presented in the etiology section). MANY DIFFERENTIAL DIAGNOSES
MSL is sometimes mistaken for “simple” truncal obesity and fruitlessly treated with a diabetic regimen. MSL may also be confused with Cushingoid syndromes. Other entities with neck masses should be considered, such as thyroid goiter, angiolipoma, neurofibromatosis, encapsulated lipoma, hibernoma, dermal spindle cell lipoma, congenital infiltrating lipomatosis, myxoid liposarcoma, lymphoma, salivary gland disorders, Fröhlich’s syndrome, Dercum’s disease and lipoblastomatosis, cystic hygroma, and branchiogenic cleft cyst in childhood.19 The lipomatosis observed in HIV-infected patients is also a differential diagnosis; it is thought to be related to hypertriglyceridemia, a consequence of protease inhibitors use.20 ASSESSMENT OF GRAVITY
The diagnosis of MSL is primarily established by physical examination and clinical history taking; it is frequently made in an advanced phase, usually because of an important esthetic disfigurement or local symptoms, such as dyspnea and dysphagia. If there is a doubt, fine-needle aspiration may be useful.21 Computed tomography and magnetic resonance imaging are helpful to document the distribution of excess fat,22,23 and in individuals with airway obstruction, to rule out possible mediastinal extension or a malignant airway tumor.24 Sonography does not provide adequate preoperative information. Some internists recommend laboratory screening for metabolic syndromes, assaying fasting glucose, cholesterol and its subfractions, triglycerides, uric acid, and liver enzymes (ALAT, ASAT, gamma GT), and performing an abdominal sonography, especially in patients with present or past alcohol abuse. An endocrine workup for Cushingoid syndromes should be considered25 if other differential diagnoses are suggested. THE ETIOLOGY REMAINS OBSCURE
It has been suggested that MSL arises from excess lipid accumulation in functionally defective embryonic brown adipose tissue.26 The distribution of the fat masses27 and the ultrastructure of the adipose cells of the lipomas28 support this hypothesis. Recently, Nisoli et al29 found that a specific molecular marker of brown adipocytes, the UCP-1 gene, was expressed in the cultured adipocytes, but not in the control adipocytes, of each of the 10 patients studied.
There is also increasing evidence that various mitochondrial dysfunctions underlie MSL.30-32 For instance, a familial form with a mitochondrial DNA abnormality, an 8344 mutation in the tRNA gene of mitochondrial DNA, has been reported.33 The reduced activity of the mitochondrial respiratory enzymes might depress the lipolytic pathway.34 According to this mechanism, MSL could be a late manifestation of a subtle mitochondrial dysfunction in a highly susceptible tissue. Alcohol seems to act as a cofactor, possibly explaining the low prevalence of MSL in children,35 but the mechanism of action is not fully understood. A lack of catecholamine-induced lipolysis of the hypertrophic adipose tissue has been reported in patients with MSL.36,37 Chronic alcohol ingestion is known to affect the -adrenergic receptors and therefore to create a dysfunction at the membrane level of lipolysis, but it has been shown that the number and function of lipomas’ -adrenergic receptors can be normal in some patients with MSL.38,39 Ethanol may directly affect mitochondrial metabolism. THE CLINICAL COURSE: A NOT SO BENIGN DISEASE
The size of the fat deposits increases over the years; many reach gigantic proportions and become cosmetically deforming. In advanced cases, dyspnea, dysphagia, and dysphonia may ensue.40 The clinical course of MSL begins with an initial period of fast growth, followed by slow progression over a long period. Until now there have been no reports of sustained regression, spontaneously or with drug therapy. MSL is a progressive disease with an infiltrative behavior that makes radical excision extremely difficult; recurrence after surgery is frequent.41,42 Patients should be followed closely because of the risk of neuropathy, even if complete remission is achieved after surgery. In addition, extensive fat tissue deposits in the pharyngeal region increase the risk of obstructive sleep apnea. Malignant transformation is extremely rare. Only 1 case of malignant degeneration has been reported in the literature.43 Although a higher risk of oropharyngeal carcinoma has been reported in patients with MSL, it may be a consequence of the associated alcohol consumption.44 Haap et al45 found that the fat deposits of 2 patients with MSL did not exhibit insulin resistance. The metabolic implications of MLS remain largely unknown, but life expectancy is reduced because of the abovementioned risks. PALLIATIVE TREATMENT: TWO SURGICAL METHODS
Surgical resection and suction-assisted lipectomy are both effective to reduce the lipomas, but com-
1368 plete removal is not feasible.46,47 The goal of the surgical treatment is to improve the cosmetic appearance and/or to treat possible upper airway obstruction. Liposuction is a safe and easy method to reduce Madelung’s lipomas or to assist conventional excisions, but can be difficult in some patients whose fatty tumors have a fibrous stroma. It can be performed safely under local anesthesia and may be recommended for patients whose poor health status would increase the risk of general anesthesia complications.48 Ultrasound guidance can be helpful.49 Liposuction enables preferential lipid emulsification and cavitation of fat, resulting in a more selective and greater volume reduction and subsequently more effective skin retraction. Besides, this technique seems to reduce postoperative bleeding. Nevertheless, it should be noted that posterior neck lipomas are usually more fibrous and difficult to draw out by suction. Some authors recommend reserving this technique for refinement of the perimandibular contour. Open excision is more effective for patients with severe cosmetic deformities.50,51 Open excisions are also safer because nerves and major vessels can be identified. A single transverse incision generally provides a better cosmetic result than several small direct incisions. Median sternotomy is needed in the event of symptomatic mediastinal lipomatosis.52 The risk of postoperative hematoma has been reported by many authors,50,53 emphasizing the need for more careful hemostasis than for other procedures. More vacuum drains are also generally needed. Intubation of patients with Madelung’s collar can be difficult because of the limited head motion, small mouth opening, or tracheal compression and displacement. A pediatric fiberoptic bronchoscope may be used as a guide for intubation.54 DRUG THERAPY IS NOT EFFECTIVE
Drug therapy with a 2-agonist (salbutamol)55 and intralesional injection of low-molecular-weight heparin56 has been advocated as an alternative treatment, but efficacy has been inconsistent. Dietary control and abstinence from alcohol are of course recommended. Although the impact may be minimal, progression of the fatty masses may be limited with a lower rate of recurrence; regression cannot be expected. Carbamazepine may be indicated to treat neuropathy in patients with MSL.57 OPTIMAL TREATMENT
MSL is a rare disorder whose pathophysiology is poorly understood. To date, palliative surgical reduction of the fatty masses is the only effective treatment available. Because the lipomas are not encapsulated and are totally surrounded by normal adipose tissue,
MULTIPLE SYMMETRIC LIPOMATOSIS
debulking lipectomy and/or liposuction can be considered as appropriate treatment for patients with esthetic deformities, psychologic problems with this disfigurement, or compressive airway or digestive tract dysfunction. The results are often less than satisfactory because of the large number of lipomas, the high rate of recurrence, and the infiltrative nature of the masses. It is difficult to identify the limits of resection. Surgery patients should be carefully monitored over a prolonged period because of the risk of recurrence. Because of the nervous system abnormalities, metabolic disturbances, and malignant tumors often associated, patients with MSL should be examined regularly and encouraged to abstain from alcohol, a risk factor for both MSL and many upper airway cancers.
References 1. Brodie BC: Clinical Lectures on Surgery Delivered at St. George’s Hospital. Philadelphia, PA, Lea and Blanchard, 1846, p 201 2. Madelung OW: Ueber Den Fetthals. Arch Klin Chir 37:106, 1888 3. Launois PE, Bensaude R: L’adénolipomatose symétrique. Bull Mem Soc Med Hosp Paris 15:298, 1898 4. Adamo C, Vescio G, Battaglia M, et al: Madelung’s disease: Case report and discussion of treatment options. Ann Plast Surg 46:43, 2001 5. Ruzicka T, Vieluf D, Landthaler M, et al: Benign symmetrical lipomatosis Launois-Bensaude. Report of ten cases and review of the literature. J Am Acad Dermatol 17:663, 1987 6. Harsch IA, Michaeli P, Hahn EG, et al: Launois-Bensaude syndrome in a female with type 2 diabetes. Med Sci Monit 9:CS5, 2003 7. Enzi G: Multiple symmetrical lipomatosis: An updated clinical report. Medicine 63:56, 1984 8. Kratz C, Lenard H-G, Ruzicka T, et al: Multiple symmetric lipomatosis: An unusual cause of childhood obesity and mental retardation. Eur J Paediatr Neurol 4:63, 2000 9. Donhauser G, Vieluf D, Ruzicka T, et al: Benigne symmetrische Lipomatose Launois-Bensaude Typ III und Bureau-Barriere-Syndrom. Der Hautartzt 42:42311, 1991 10. Soler R, Requejo I, Fontán M, et al: MR of laryngeal and scrotal involvement in multiple symmetrical lipomatosis. Eur Radiol 7:946, 1997 11. Moretti JA, Miller D: Laryngeal involvement in benign symmetrical lipomatosis (Madelung’s disease). Arch Otolaryngol 97: 495, 1973 12. Enzi G, Biondetti PR, Fiore D, et al: Computed tomography of deep fat masses in multiple symmetric lipomatosis. Radiology 144:121, 1982 13. Vargas-Díez E, Dauden E, et al: Madelung’s disease involving the tongue. J Am Acad Dermatol 42:511, 2000 14. Harsch IA, Schahin SP, Fuchs FS, et al: Insulin resistance, hyperleptinemia, and obstructive sleep apnea in Launois-Bensaude syndrome. Obesity Res 10:625, 2002 15. Iglesias L, Pérez-Llantada E, Saro G, et al: Benign symmetrical lipomatosis (Madelung’s disease). Eur J Intern Med 11:171, 2000 16. Pollack M, Nicholson GI, Nukada H: Neuropathy in multiple symmetric lipomatosis. Brain 111:1157, 1988 17. Saiz-Hervás E, Marín Llorens M, López Álvarez J: Peripheral neuropathy as the first manifestation of Madelung’s disease. Br J Dermatol 143:684, 2000 18. Grosshans EM, Le Coz CJ: Alcohol intake, lipid metabolism, and the skin. Clin Dermatol 17:413, 1999
MENINGAUD, PITAK-ARNNOP, AND BERTRAND 19. Greene M, Glueck C, Fujimoto W, et al: Benign symmetrical lipomatosis (Launois-Bensaude adenolipomatosis) with gout and hyperlipoproteinemia. Am J Med 48:239, 1970 20. Williamson K, Reboli AC, Mander SM: Protease inhibitor-induced lipodystrophy. J Am Acad Dermatol 40:635, 1999 21. Josephson GD, Sclafani AP, Stern J: Benign symmetric lipomatosis (Madelung’s disease). Otolaryngol Head Neck Surg 115: 170, 1996 22. Ahuja AT, King AD, Chan ES, et al: Madelung’s disease: Distribution of cervical fat and preoperative findings at sonography, MR, and CT. AJNR Am J Neuroradiol 19:707, 1998 23. Feldman DR, Schabel SI: Multiple symmetrical lipomatosis: Computed tomographic appearance. South Med J 88:681, 1995 24. Ahuja AT, King AD, Chan ES: Ultrasound, CT and MRI in patients with multiple symmetric lipomatosis. Clin Radiol 55: 79, 2000 25. Baynosa RC, Shah HR, Khiabani KT, et al: Ultrasound-assisted liposuction in the treatment of lipodystrophy secondary to Cushingoid-type disease of unknown cause. Plast Reconstr Surg 114:474, 2004 26. Vilà MR, Gámez J, Solano A, et al: Uncoupling protein-1 mRNA expression in lipomas from patients bearing pathogenic mitochondrial DNA mutations. Biochem Biophys Res Commun 278: 800, 2000 27. Kodish ME, Alsever RN, Block MB: Benign symmetric lipomatosis: Functional sympathetic denervation of adipose tissue and possible hypertrophy of brown fat. Metabolism 23:937, 1974 28. Zancanaro C, Sbarbati A, Morroni M, et al: Multiple symmetric lipomatosis: Ultrastructural investigation of the tissue and preadipocytes in primary culture. Lab Invest 63:253, 1990 29. Nisoli E, Regianini L, Briscini L, et al: Multiple symmetric lipomatosis may be the consequence of defective noradrenergic modulation of proliferation and differentiation of brown fat cells. J Pathol 198:378, 2002 30. Berkovic SF, Andremann F, Shoubridge EA: Mitochondrial dysfunction in multiple symmetrical lipomatosis. Ann Neurol 29: 566, 1991 31. Klopstock T, Naumann M, Schalke B, et al: Multiple symmetrical lipomatosis: Abnormalities in complex IV and multiple deletions in mitochondrial DNA. Neurology 44:862, 1994 32. Campos Y, Martin MA, Navarro C, et al: Single large-scale mitochodrial DNA deletion in a patient with mitochondrial myopathy associated with multiple symmetric lipomatosis. Neurology 47:1012, 1996 33. Gamez J, Playan A, Andreu AL, et al: Familial multiple symmetric lipomatosis associated with the A8344G mutation of mitochondria DNA. Neurology 51:258, 1998 34. Becker-Wegerich P, Steuber M, Olbrisch R, et al: Defects of mitochondrial respiratory chain in multiple symmetric lipomatosis. Arch Dermatol Res 290:652, 1998 35. Nounla J, Rolle U, Gräfe G, et al: Benign symmetric lipomatosis with myelomeningocele in an adolescent: An uncommon association–Case report. J Paediatr Surg 36:1, 2001 36. Enzi G, Inelman EM, Baritussio A, et al: Multiple symmetric lipomatosis: A defect in adrenergic-stimulated lipolysis. J Clin Invest 60:1221, 1977 37. Desai KS, Zinman B, Steiner G: Multiple symmetrical lipomatosis (Launois-Bensaude syndrome). Adipose tissue insensitivity to cyclic AMP. J Clin Endocrinol Metab 49:307, 1979
1369 38. Pecquery R, Malagrida L, Guidicelli Y: Adipocytic adenylate cyclase and alpha- and beta-adrenergic receptors in one case of multiple symmetric lipomatosis. Biomedicine 33:64, 1980 39. Kather H, Schroder F: Adrenergic regulation of fat-cell lipolysis in multiple symmetric lipomatosis. Eur J Clin Invest 12:471, 1982 40. Birnholz JC, Alexander S, Macmillan JR: Advanced laryngeal compression due to diffuse, symmetric lipomatosis (Madelung’s disease). Br J Radiol 46:245, 1973 41. Argenta LC, Mcclatchey KD, Ferrel WJ, et al: Benign symmetrical lipomatosis (Madelung’s disease). Head Neck Surg 3:240, 1981 42. Gabriel YA, Chew DKW, Wedderburn RV: Multiple symmetrical lipomatosis (Madelung’s disease). Surgery 129:117, 2001 43. Tizian C, Berger A, Vykoupil KF: Malignant degeneration in Madelung’s disease (benign lipomatosis of the neck): Case report. Br J Plast Surg 36:187, 1983 44. Guastella C, Borsi C, Gibelli S, et al: Madelung’s lipomatosis associated with head and neck malignant neoplasia: A study of 2 cases. Otolaryngol Head Neck Surg 126:191, 2002 45. Haap MH, Siewecke C, Thamer C, et al: Multiple symmetric lipomatosis. A paradigm of metabolically innocent obesity? Diabetes Care 27:794, 2004 46. Fernández Sanromán J, Díaz González F, Rodríguez Campo FJ: Benign symmetrical lipomatosis with mediastinal involvement and growth retardation. J Oral Maxillofac Surg 50:299, 1992 47. Kohan D, Miller PJ, Rothstein SG, et al: Madelung’s disease: Case reports and literature review. Otolaryngol Head Neck Surg 108:156, 1993 48. Parmar C, Blackburn C: Madelung’s disease: An uncommon disorder of unknown aetiology? Br J Oral Maxillofac Surg 34: 467, 1996 49. Faga A, Valdatta LA, Thione A, et al: Ultrasound assisted liposuction for the palliative treatment of Madelung’s disease: A case report. Aesth Plast Surg 25:181, 2001 50. Wong DS, Lam LK, Chung JH, et al: Aesthetic considerations in the cervicofacial management of Madelung’s syndrome. Scand J Plast Reconstr Surg Hand Surg 37:34, 2003 51. González-García R, Rodríguez-Campo FJ, Sastre-Pérez J, et al: Benign symmetric lipomatosis (Madelung’s disease): Case reports and current management. Aesthetic Plast Surg 28:108, 2004 52. Brackenbury ET, Morgan WE: Surgical management of LaunoisBensaude syndrome. Thorax 52:834, 1997 53. Boozan JA, Maves MD, Schuller DE: Surgical management of massive benign symmetric lipomatosis. Laryngoscope 102:94, 1992 54. Morinaka S, Sato T, Miyoshi H, et al: A case of multiple symmetrical lipomatosis (Madelung’s disease). Auris Nasus Larynx 26:349, 1999 55. Leung N, Gaer J, Beggs D, et al: Multiple symmetrical lipomatosis (Launois-Bensaude syndrome): Effect of oral salbutamol. Clin Endocrin 7:601, 1987 56. Fisher M, Wohlrab J, Taube KM, et al: Intralesional injection of enoxaparin in benign symmetrical lipomatosis: An alternative to surgery? Br J Dermatol 144:629, 2001 57. Preisz K, Karpati S, Horvath A: Launois-Bensaude syndrome and Bureau-Barriere syndrome in a psoriatic patient: Successful treatment with carbamazepine. Eur J Dermatol 12:267, 2002
MENINGAUD, PITAK-ARNNOP, AND BERTRAND
J Oral Maxillofac Surg 65:1365-1369, 2007
Multiple Symmetric Lipomatosis: Case Report and Review of the Literature Jean-Paul Meningaud, MD, PhD, FEBOMS,* Poramate Pitak-Arnnop, DDS, Diploma(OMS),† and Jacques-Charles Bertrand, MD‡ Multiple symmetric lipomatosis (MSL) is a rare disease mainly characterized by large subcutaneous fatty masses distributed around the neck, shoulders, upper extremities, and upper dorsal regions. Sir Benjamin Brodie first described MSL in 1846,1 but Otto Madelung described the first case series in 1888 (35 cases).2 The following decade, Pierre Emile Launois and Raoul Bensaude presented a larger case series of 65 patients.3 Since then, approximately 200 cases have been published in the medical literature.4 MSL has been designated by several different names, including Madelung’s disease, Launois-Bensaude’s disease, symmetrical adenolipomatosis, benign symmetrical lipomatosis, lipoma diffusa symmetrica, and lipomatosis simplex indolens. The aims of this article are to report the sequential management of a 50-year-old French patient with MSL and to provide a comprehensive and thorough overview of the current concepts concerning this disease with an emphasis on understanding the etiologies and modalities of treatment.
Report of a Case The patient was a 50-year-old French man (height 1.69 m, weight 69 kg) with a history of alcohol abuse, heavy smoking, and 2 surgical procedures for vertebral disc herniation performed 2 and 4 years earlier. One of his uncles had MSL. The patient was referred to the maxillofacial surgery department with a 5-year history of massive, painless lipomas diffusely distributed over his neck, limiting head motion. On
Received from the Department of Maxillofacial Surgery, PitiéSalpêtrière Hospital, Paris, France. *Consultant, Maxillofacial Surgeon. †Surgical Fellow. ‡Professor and Head. Address correspondence and reprint requests to Dr Meningaud: Service de Chirurgie Maxillo-Faciale, CHU Pitié-Salpêtrière, 47 bd de l’hôpital, 75651 Paris, Cedex 13, France; e-mail: [email protected] © 2007 American Association of Oral and Maxillofacial Surgeons
0278-2391/07/6507-0018$32.00/0 doi:10.1016/j.joms.2005.10.045
palpation, the fat deposits had a soft consistency. A large posterior cervical lipoma formed a continuous mass with anterolateral deposits (Fig 1). In addition, he had several small lipomas located bilaterally in his shoulders. No cervical lymph nodes were palpable and the masses could not be transilluminated. There were no signs of dyspnea, dysphagia, or dysphonia. The remaining clinical examination and routine laboratory tests were unremarkable except for elevated gamma GT values. Computed tomography scan confirmed the presence of extensive masses with fat density in the referred area without mediastinal involvement (Fig 2). Considering the extent of disease, a 3-stage lipectomy with a 2-month interval was proposed to the patient. Lipectomies were performed via open cervical approaches; each operation removed one third of the total mass. Intraoperatively, the fat was nonencapsulated; it infiltrated normal subcutaneous fat and was intertwined with carotid arteries and jugular veins. The weights of the excised specimens were 280, 430, and 300 g. Histologic studies were consistent with the clinical diagnosis. They showed a proliferation of large, empty-appearing cells with compressed nuclei, typical of adipocytes with a slight increase of connective tissue. There was no cellular atypia or areas of necrosis. They exhibited large adult fat cells within a normal amount of intercellular connective tissue. No abnormal intracellular constituents were identified. Three hours after the first lipectomy, the postoperative course was marked by a large hematoma producing dyspnea; surgical evacuation was performed immediately. Instead of 1 vacuum drain for the first operation, 3 vacuum drains were used for the second and third operations. Otherwise, outcomes were unremarkable with a good functional and esthetic result (Fig 3). Abstinence from alcohol was strongly recommended but was refused by the patient. Nevertheless, no recurrence was noted at the 18-month follow-up visit.
Discussion and Overview of the Literature EPIDEMIOLOGY: A RARE DISEASE
Epidemiologically, the incidence of MSL is highest in males with a history of alcohol abuse.5 However, chronic alcoholism is considered as an important but not indispensable pathogenic factor.6 MSL was found in association with alcohol in 60% to 90% in different series. The male to female ratio has been reported to be as high as 15:1.5 Onset occurs predominantly in the third, fourth, and fifth decades of life,7 but cases
1366
MULTIPLE SYMMETRIC LIPOMATOSIS
FIGURE 1. A, Anterior, and B, right lateral preoperative photographs of a patient with MSL.
FIGURE 3. A, Anterior, and B, right lateral postoperative photographs of a patient with MSL.
Meningaud, Pitak-Arnnop, and Bertrand. Multiple Symmetric Lipomatosis. J Oral Maxillofac Surg 2007.
Meningaud, Pitak-Arnnop, and Bertrand. Multiple Symmetric Lipomatosis. J Oral Maxillofac Surg 2007.
of pediatric patients have been reported.8 The general incidence is unknown, but the prevalence may be higher in Mediterranean countries (notably in Italy, Spain, and France) where most of the reported cases come from including the present case. A DIAGNOSIS MAINLY ESTABLISHED BY PHYSICAL EXAMINATION
The patient’s appearance is usually characterized by the presence of symmetrical accumulation of multiple painless unencapsulated lipomas that frequently encircle vital anatomic structures, predominately in the neck and upper extremities. The patient can have more than 1,000 lipomas of various diameters ranging in size from 1 to 20 cm in different regions of the body. Donhauser et al9 distinguish 3 types of MSL: 1) horse collar lipoma, 2) pseudoathletic appearance, and 3) gynecoid type. Features of more than 1 type can be found in some patients. The patient reported here had horse collar lipoma. The Madelung’s collar is usually symmetrical, slowly progressive, and asymptomatic with the ex-
FIGURE 2. Computed tomography scan of the neck shows a continuous fatty mass formed by a large posterior cervical lipoma and anterolateral lipomas. Density measurements were consistent with fat tissue. Meningaud, Pitak-Arnnop, and Bertrand. Multiple Symmetric Lipomatosis. J Oral Maxillofac Surg 2007.
ception of difficulties in turning the head. However, cases of deep infiltration of mediastinal structures with compression of major vessels, nerves, trachea, mainstream bronchi and esophagus leading to dyspnea, dysphagia, and dysphonia have been reported. In addition, the larynx can be narrowed by direct compression, by fatty infiltration of the larynx itself,10,11 and by infiltration or compression of recurrent laryngeal nerves.12 Involvement of the tongue in the form of macroglossia has also been reported.13 Deposit of lipomatous tissue in the pharyngeal region is probably a factor favoring obstructive sleep apnea; thus, greater care should be taken in patients with horse collar lipoma and symptoms of daytime sleepiness.14 MSL may be associated with metabolic diseases in obese patients (impaired fasting glucose control, diabetes mellitus, hyperlipidemia, and so on), but the majority of patients with MSL are not obese. Patients with MSL frequently have a history of alcohol abuse, but there is no clear relation between lipomata growth and onset or end of alcohol consumption. However, the disease is often associated with the sequels of alcohol abuse (ie, hepatopathy,15 hyperuricemia, hyperlipidemia, macrocytic anemia, and oral cancer). The neuropathy has often been attributed to alcohol toxicity, but seems in reality to be a complication of the lipoma itself. The microscopic findings in many cases of MSL are progressive axonal atrophy, whereas the histologic hallmarks of alcoholic neuropathy are axonal degeneration and demyelination.16,17 Besides, such neuropathies can be observed in patients with MSL who are not alcohol addicts,18 and notably in children.8 The polyneuropathy described as sensory, motor, or autonomic dysfunction is noted in up to 85% of cases, 80% of which develop a physical disability. Polyneuropathy develops several years after onset of MSL. Under light microscopy, histology samples exhibit the morphology of simple lipoma (Fig 3). Adipocytes look like mature monovacuolar adipocytes of white fat surrounded by connective tissue of variable den-
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MENINGAUD, PITAK-ARNNOP, AND BERTRAND
sity. The only slight difference is that they are on average smaller than normal adipocytes from the same patient. Nevertheless, electron microscopy examination of adipocyte and cultured preadipocyte ultrastructures reveals features of brown fat (more details presented in the etiology section). MANY DIFFERENTIAL DIAGNOSES
MSL is sometimes mistaken for “simple” truncal obesity and fruitlessly treated with a diabetic regimen. MSL may also be confused with Cushingoid syndromes. Other entities with neck masses should be considered, such as thyroid goiter, angiolipoma, neurofibromatosis, encapsulated lipoma, hibernoma, dermal spindle cell lipoma, congenital infiltrating lipomatosis, myxoid liposarcoma, lymphoma, salivary gland disorders, Fröhlich’s syndrome, Dercum’s disease and lipoblastomatosis, cystic hygroma, and branchiogenic cleft cyst in childhood.19 The lipomatosis observed in HIV-infected patients is also a differential diagnosis; it is thought to be related to hypertriglyceridemia, a consequence of protease inhibitors use.20 ASSESSMENT OF GRAVITY
The diagnosis of MSL is primarily established by physical examination and clinical history taking; it is frequently made in an advanced phase, usually because of an important esthetic disfigurement or local symptoms, such as dyspnea and dysphagia. If there is a doubt, fine-needle aspiration may be useful.21 Computed tomography and magnetic resonance imaging are helpful to document the distribution of excess fat,22,23 and in individuals with airway obstruction, to rule out possible mediastinal extension or a malignant airway tumor.24 Sonography does not provide adequate preoperative information. Some internists recommend laboratory screening for metabolic syndromes, assaying fasting glucose, cholesterol and its subfractions, triglycerides, uric acid, and liver enzymes (ALAT, ASAT, gamma GT), and performing an abdominal sonography, especially in patients with present or past alcohol abuse. An endocrine workup for Cushingoid syndromes should be considered25 if other differential diagnoses are suggested. THE ETIOLOGY REMAINS OBSCURE
It has been suggested that MSL arises from excess lipid accumulation in functionally defective embryonic brown adipose tissue.26 The distribution of the fat masses27 and the ultrastructure of the adipose cells of the lipomas28 support this hypothesis. Recently, Nisoli et al29 found that a specific molecular marker of brown adipocytes, the UCP-1 gene, was expressed in the cultured adipocytes, but not in the control adipocytes, of each of the 10 patients studied.
There is also increasing evidence that various mitochondrial dysfunctions underlie MSL.30-32 For instance, a familial form with a mitochondrial DNA abnormality, an 8344 mutation in the tRNA gene of mitochondrial DNA, has been reported.33 The reduced activity of the mitochondrial respiratory enzymes might depress the lipolytic pathway.34 According to this mechanism, MSL could be a late manifestation of a subtle mitochondrial dysfunction in a highly susceptible tissue. Alcohol seems to act as a cofactor, possibly explaining the low prevalence of MSL in children,35 but the mechanism of action is not fully understood. A lack of catecholamine-induced lipolysis of the hypertrophic adipose tissue has been reported in patients with MSL.36,37 Chronic alcohol ingestion is known to affect the -adrenergic receptors and therefore to create a dysfunction at the membrane level of lipolysis, but it has been shown that the number and function of lipomas’ -adrenergic receptors can be normal in some patients with MSL.38,39 Ethanol may directly affect mitochondrial metabolism. THE CLINICAL COURSE: A NOT SO BENIGN DISEASE
The size of the fat deposits increases over the years; many reach gigantic proportions and become cosmetically deforming. In advanced cases, dyspnea, dysphagia, and dysphonia may ensue.40 The clinical course of MSL begins with an initial period of fast growth, followed by slow progression over a long period. Until now there have been no reports of sustained regression, spontaneously or with drug therapy. MSL is a progressive disease with an infiltrative behavior that makes radical excision extremely difficult; recurrence after surgery is frequent.41,42 Patients should be followed closely because of the risk of neuropathy, even if complete remission is achieved after surgery. In addition, extensive fat tissue deposits in the pharyngeal region increase the risk of obstructive sleep apnea. Malignant transformation is extremely rare. Only 1 case of malignant degeneration has been reported in the literature.43 Although a higher risk of oropharyngeal carcinoma has been reported in patients with MSL, it may be a consequence of the associated alcohol consumption.44 Haap et al45 found that the fat deposits of 2 patients with MSL did not exhibit insulin resistance. The metabolic implications of MLS remain largely unknown, but life expectancy is reduced because of the abovementioned risks. PALLIATIVE TREATMENT: TWO SURGICAL METHODS
Surgical resection and suction-assisted lipectomy are both effective to reduce the lipomas, but com-
1368 plete removal is not feasible.46,47 The goal of the surgical treatment is to improve the cosmetic appearance and/or to treat possible upper airway obstruction. Liposuction is a safe and easy method to reduce Madelung’s lipomas or to assist conventional excisions, but can be difficult in some patients whose fatty tumors have a fibrous stroma. It can be performed safely under local anesthesia and may be recommended for patients whose poor health status would increase the risk of general anesthesia complications.48 Ultrasound guidance can be helpful.49 Liposuction enables preferential lipid emulsification and cavitation of fat, resulting in a more selective and greater volume reduction and subsequently more effective skin retraction. Besides, this technique seems to reduce postoperative bleeding. Nevertheless, it should be noted that posterior neck lipomas are usually more fibrous and difficult to draw out by suction. Some authors recommend reserving this technique for refinement of the perimandibular contour. Open excision is more effective for patients with severe cosmetic deformities.50,51 Open excisions are also safer because nerves and major vessels can be identified. A single transverse incision generally provides a better cosmetic result than several small direct incisions. Median sternotomy is needed in the event of symptomatic mediastinal lipomatosis.52 The risk of postoperative hematoma has been reported by many authors,50,53 emphasizing the need for more careful hemostasis than for other procedures. More vacuum drains are also generally needed. Intubation of patients with Madelung’s collar can be difficult because of the limited head motion, small mouth opening, or tracheal compression and displacement. A pediatric fiberoptic bronchoscope may be used as a guide for intubation.54 DRUG THERAPY IS NOT EFFECTIVE
Drug therapy with a 2-agonist (salbutamol)55 and intralesional injection of low-molecular-weight heparin56 has been advocated as an alternative treatment, but efficacy has been inconsistent. Dietary control and abstinence from alcohol are of course recommended. Although the impact may be minimal, progression of the fatty masses may be limited with a lower rate of recurrence; regression cannot be expected. Carbamazepine may be indicated to treat neuropathy in patients with MSL.57 OPTIMAL TREATMENT
MSL is a rare disorder whose pathophysiology is poorly understood. To date, palliative surgical reduction of the fatty masses is the only effective treatment available. Because the lipomas are not encapsulated and are totally surrounded by normal adipose tissue,
MULTIPLE SYMMETRIC LIPOMATOSIS
debulking lipectomy and/or liposuction can be considered as appropriate treatment for patients with esthetic deformities, psychologic problems with this disfigurement, or compressive airway or digestive tract dysfunction. The results are often less than satisfactory because of the large number of lipomas, the high rate of recurrence, and the infiltrative nature of the masses. It is difficult to identify the limits of resection. Surgery patients should be carefully monitored over a prolonged period because of the risk of recurrence. Because of the nervous system abnormalities, metabolic disturbances, and malignant tumors often associated, patients with MSL should be examined regularly and encouraged to abstain from alcohol, a risk factor for both MSL and many upper airway cancers.
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