Background

This is a rare syndrome characterized by distinctive pattern of skin involvement that spares the digits, involves fascia rather than dermis, and is not accompanied by Raynaud phenomenon. Many investigators believe it represents a variant of scleroderma. The classic components include peripheral blood eosinophilia, elevated sedimentation rate, hypergammaglobulinemia, and fascial thickening. Rarely internal organs may be involved, but these cases are usually mild. In rare cases, a fatal aplastic anemia may occur.

OUTLINE

Epidemiology
Disease Associations	Lymphoma Renal failure
Pathogenesis	Borrelia
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants	Lungs Peripheral neuropathy Skin
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis	Eosinophilia-Myalgia syndrome Toxic oil syndrome
Prognosis
Treatment	Surgery Transplantation, Bone Marrow
Commonly Used Terms
Internet Links

 

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Schulman syndrome

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
GRAFT VERSUS HOST DISEASE
Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft-versus-host disease: expanding the sclerodermoid spectrum. Schaffer JV, McNiff JM, Seropian S, Cooper DL, Bolognia JL. Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.	J Am Acad Dermatol. 2005 Oct;53(4):591-601. Abstract quote   Chronic cutaneous graft-versus-host disease (GVHD) is classically divided into two major clinical categories--lichenoid and sclerodermoid. Although diffuse areas of sclerosis as in scleroderma characterize the more advanced stages of the sclerodermoid form, the initial circumscribed plaques would be more correctly described as morpheaform. Eosinophilic fasciitis (EF) (a fibrosing disorder related to deep morphea) and lichen sclerosus (LS) have also been reported as manifestations of sclerodermoid GVHD. However, these two presentations of GVHD have not been emphasized in the dermatologic literature. We describe 6 patients, all of whom developed LS and two of whom also developed EF in the context of chronic GVHD. Each patient presented clinically with hypopigmented plaques that exhibited wrinkling, scaling, and follicular plugging. These lesions demonstrated the classic histologic features of LS including epidermal atrophy; a subepidermal zone of pale-staining, homogenized collagen; and a bandlike lymphocytic infiltrate. Although all patients eventually developed morpheaform and/or sclerodermoid GVHD, LS was a prominent part of the initial presentation of chronic cutaneous GVHD in every case. The LS lesions tended to occur on the neck and upper to mid aspect of the trunk, whereas morpheaform lesions favored the lower aspect of the trunk. EF involved the extremities (sparing the hands and feet), and was characterized clinically by an acute onset of pain and edema followed by induration with a rippled appearance. This case series serves to expand the spectrum of sclerodermoid GVHD, with LS as the most superficial and EF as its deepest manifestation.
LYMPHOMA
Lymph-node-based malignnt lymphoma and reactive lymphadenopathy in eosinophilic fasciitis. Naschitz JE, Misselevich I, Rosner I, Yeshurun D, Weiner P, Amar M, Amato L, Ciompi ML, Boss JH. Department of Internal Medicine, Bnai-Zion Medical Center, Haifa, Israel.	Am J Med Sci 1999 Nov;318(5):343-9 Abstract quote BACKGROUND: Lymph node enlargement in patients with eosinophilic fasciitis is a rare occurrence and its clinical significance is unknown. METHODS: The literature and authors' registries were searched for eosinophilic fasciitis associated with lymphadenopathy. Clinical data, time sequence of appearance of either disorder, and pathological diagnoses were analyzed. RESULTS: Six patients presenting with eosinophilic fasciitis had a lymph-node-based lymphoma and 4 patients had a reactive lymphadenopathy. The patients with lymphoma were elderly and the subcutaneous induration preceded the lymphadenopathy by 2 to 36 months. The patients with eosinophilic fasciitis and reactive lymphadenopathy were young and the onset of subcutaneous induration and lymph node enlargement coincided with one another. Favorable response of the eosinophilic fasciitis to prednisone therapy was attained in 3 of 3 patients with reactive lymphadenopathy and in 4 of the 6 cases with lymphoma. CONCLUSIONS: Eosinophilic fasciitis is rarely associated with clinically significant lymph node enlargement. Subcutaneous induration preceding the lymphadenopathy by 6 months or more, especially in elderly patients, suggests an underlying lymphoma. A favorable response of the subcutaneous induration to prednisone treatment does not exclude the diagnosis of lymphoma; therefore, it does not supersede the need of a pathological evaluation. A lymph node biopsy is mandatory in all cases.
RENAL FAILURE
Eosinophilic fasciitis occurring four weeks after the onset of dialysis in a renal failure patient. Florell SR, Egan CA, Gregory MC, Zone JJ, Petersen MJ. Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City 84132, USA.	J Cutan Med Surg 2001 Jan-Feb;5(1):33-6 Abstract quote BACKGROUND: Eosinophilic fasciitis is a rare, scleroderma-like disease that usually affects the extremities of young to middle-aged males. The disease may cause flexion contractures and limit joint mobility and is associated with peripheral eosinophilia. The fascia, by definition, is infiltrated with mononuclear cells and typically with eosinophils. Eosinophilic fasciitis may be separated from another sclerodermatous disorder, linear scleroderma, by its response to systemic corticosteroids. The etiology is unclear but eosinophilic fasciitis has numerous disease associations. However, it has not previously been associated with renal failure and hemodialysis. OBJECTIVE: This article reports a case of eosinophilic fasciitis occurring four weeks following the onset of hemodialysis. METHODS: The clinical and histologic features confirmed the diagnosis of eosinophilic fasciitis. He was treated with systemic corticosteroids with good response. CONCLUSION: This is the first reported patient who developed eosinophilic fasciitis in close temporal relationship with the start of hemodialysis. While eosinophilic fasciitis may be coincidental with a common disorder, namely, renal failure, it is interesting to note that hemodialysis patients often have immune-regulation abnormalities and peripheral eosinophilia.

 

PATHOGENESIS	CHARACTERIZATION
BORRELIA
Polymerase chain reaction of Borrelia burgdorferi flagellin gene in Shulman syndrome. Hashimoto Y, Takahashi H, Matsuo S, Hirai K, Takemori N, Nakao M, Miyamoto K, Iizuka H. Department of Dermatology, Asahikawa Medical College, Japan	Dermatology 1996;192(2):136-9 Abstract quote A 49-year-old man presented a progressive swelling and induration of the skin resulting in flexion contracture. He had a history of two tick bites at the age of 17 and 47 years. Serum anti-Borrelia-burgdorferi antibody was positive; isolation of B. burgdorferi from the skin lesion was unsuccessful. He had eosinophilia (white blood cells 8,300/microlitre, 33% eosinophils) and hypergammaglobulinemia. The diagnosis of Shulman syndrome (eosinophilic fasciitis) from clinical and histological findings was established. A part of the flagellin gene of B. burgdorferi was detected in a skin biopsy sample by using the polymerase chain reaction method. To the best of our knowledge, this is the first report of detection of B.-burgdorferi-specific DNA from a skin sample of Shulman syndrome.

 

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
MRI
Eosinophilic fasciitis in a military recruit: MRI evaluation with clinical correlation. Liou CH, Huang GS, Taylor JA, Juan CJ, Gao HW, Chen CY. Department of Radiology, Tri-Service General Hospital & National Defense Medical Center, Taipei, Taiwan, R.O.C.	Skeletal Radiol 2003 Jan;32(1):52-7 Abstract quote Eosinophilic fasciitis (EF) is an uncommon connective tissue disease. We report a patient with EF who presented with episodic swelling and stiffness of his legs and forearms in combination with peripheral eosinophilia. Imaging studies of the legs and forearms, including computed tomography (CT) and magnetic resonance imaging (MRI), clearly demonstrated the characteristic finding of fascial thickening. The complete clinical imaging and pathological findings are described in this report. Cross-sectional imaging is useful in diagnosing EF and in the appropriate clinical scenario may be helpful in differentiating EF from other connective tissue diseases.
Use of magnetic resonance imaging in diagnosing eosinophilic fasciitis. Report of two cases. al-Shaikh A, Freeman C, Avruch L, McKendry RJ. University of Ottawa, Ontario, Canada.	Arthritis Rheum 1994 Nov;37(11):1602-8 Abstract quote OBJECTIVE. To determine the role of magnetic resonance imaging (MRI) in the diagnosis of eosinophilic fasciitis (EF), selection of appropriate biopsy site, and followup of treatment. METHODS. MRI was used to examine 2 patients with EF at the time of their initial clinical presentation and after several months of treatment. T2-weighted axial, T2-weighted axial with fat saturation, and T1-weighted axial post-gadolinium with fat saturation scans at 1.5T were obtained. RESULTS. MRI demonstrated hyperintensity within the fascia. This defect resolved with treatment and clinical improvement. CONCLUSION. MRI is a useful noninvasive tool for diagnosing EF and for monitoring the effectiveness of therapy.
LABORATORY MARKERS
Association of eosinophilic fasciitis, multiple morphea and antiphospholipid antibody. Castanet J, Lacour JP, Perrin C, Taillan B, Dubois D, Ortonne JP. Department of Dermatology, University of Nice, France	Dermatology 1994;189(3):304-7 Abstract quote The occurrence of morphea-like changes during the course of eosinophilic fasciitis is considered to be rare. We observed such a case with simultaneous occurrence of both types of lesions. Histologically, fibrosis and inflammatory infiltrate were seen in the entire dermis, the subcutis and the fascia, suggesting that the same process might account for all skin changes. In addition, our patient had an antiphospholipid antibody, neurologic symptoms and livedo-like cutaneous lesions. However, whether the antiphospholipid antibody played a pathogenic role or not remains unclear. Corticosteroid treatment was successful.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
LUNGS
Eosinophilic fasciitis with pulmonary and pleural involvement. Killen JW, Swift GL, White RJ. Department of Medicine, Frenchay Hospital, Bristol, BS16 1LE, UK.	Postgrad Med J 2000 Jan;76(891):36-7 Abstract quote We report a case of eosinophilic fasciitis, with the unusual features of pulmonary and pleural involvement. Similar cases which involve the lungs have been reported after exposure to L-tryptophan, but there is no relevant drug history in this case.
PERIPHERAL NEUROPATHY
Eosinophilic fasciitis complicated with peripheral polyneuropathy. Moriguchi M, Terai C, Kuroki S, Tanaka E, Someya N, Tsunoda Y, Kashiwazaki S. Institute of Rheumatology, Tokyo Women's Medical College.	Intern Med 1998 Apr;37(4):417-20 Abstract quote Peripheral polyneuropathy and the complication of eosinophilic fasciitis (EF) is rare; only 2 such cases have been described previously. A 40-year-old woman suffered from swelling of the extremities after strenuous exercise and complained of bilateral paresthesia on the soles of her feet. The diagnosis was EF according to clinical symptoms, peripheral eosinophilia, and histological examination of the fascia. Nerve conduction tests also revealed sensory disturbance as mononeuritis multiplex. After administration of prednisolone, the swelling and tenderness of the extremities improved immediately but the neuropathy lasted for 6 months.
SKIN
Eosinophilic fasciitis (Shulman syndrome). Mosconi S, Streit M, Bronimann M, Braathen LR. Dermatological Clinic, Inselspital, University of Berne, Switzerland	Dermatology 2002;205(2):204-6 Abstract quote We report a case of a 30-year-old Caucasian patient with progressive sclerosis of the skin mainly on the upper limbs which was diagnosed as eosinophilic fasciitis (Shulman syndrome). Circulating antibodies against Borrelia burgdorferi were detected. The association of B. burgdorferi infection with eosinophilic fasciitis is discussed.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
NEUROMUSCULAR
The neuromuscular pathology of the Eosinophilia-Myalgia syndrome. Seidman RJ, Kaufman LD, Sokoloff L, Miller F, Iliya A, Peress NS. Department of Pathology, State University of New York, Stony Brook 11794-8691.	J Neuropathol Exp Neurol 1991 Jan;50(1):49-62 Abstract quote The Eosinophilia-Myalgia Syndrome (EMS) is a recently reorganized disorder in patients ingesting pharmacologic doses of L-tryptophan. We studied the lesions of skeletal muscle, peripheral nerve and skin in 12 cases of EMS. Perimyositis was severe in four, moderate in two, mild in three and absent in three cases. The lesions contained many eosinophils, T-helper cells, mast cells and activated macrophages. Type 2 myofiber atrophy was present in five cases and in one, this was the only pathologic finding. Severe epineurial inflammation was seen in the three sural nerve biopsies. Indirect evidence for peripheral neurologic involvement in three other cases consisted of inflammation surrounding intramuscular nerve twigs (two cases) and neurogenic atrophy (one case). Phlebitis accompanied the connective tissue inflammation in five cases and endarteritis in one. Fasciitis was present in three of four skin biopsies and dermal fibrosis in one.
SKIN
Comparison of the pathology of fascia in eosinophilic myalgia syndrome patients and idiopathic eosinophilic fasciitis. Umbert I, Winkelmann RK, Wegener L. Department of Dermatopathology and Laboratory Medicine, Mayo Clinic, Scottsdale, Ariz.	Dermatology 1993;186(1):18-22 Abstract quote The L-tryptophan eosinophilic myalgia syndrome (EMS) clinically has some similarities with idiopathic eosinophilic fasciitis (EF). In order to study the pathology of both syndromes, we analyzed 21 biopsies of patients with EMS and 8 with idiopathic EF. In both diseases there is dermal and fascial mucin and dermal edema, but this was more common in EMS. EMS is also characterized by dilated lymphatics, dermal and septal sclerosis and macrophage-rich inflammation. Neural inflammation was seen in 4 of the cases with EMS and in none with idiopathic EF. In both syndromes, there are many histopathological similarities. The differences may be due to sampling and to sample size. The nerve lesions of EMS may result from the nature of lymphocyte-macrophage inflammation, or the effect of the eosinophil neurotoxin and may not be a primary event.
Pathologic manifestations of the eosinophilia myalgia syndrome: analysis of 11 cases. Lin JD, Phelps RG, Gordon ML, Hilfer JB, Wolfe DE, Venkataseshan VS, Fleischmajer R. Department of Dermatology, Mount Siani School of Medicine, New York, NY.	Hum Pathol 1992 Apr;23(4):429-37 Abstract quote We describe the histopathologic changes of skin, muscle, vessels, and fascia in 11 patients with eosinophilia myalgia syndrome, a newly described entity that has been linked to the ingestion of L-tryptophan. This syndrome is defined clinically by severe incapacitating myalgias and a peripheral eosinophilia. Arthralgias, edema of the extremities, morbilliform rashes, skin induration, weakness, fatigue, and respiratory weakness may be present as well. The earliest apparent histologic changes were observed at the septa between subcutaneous fat lobules and in the deep dermis or fascia. The septa and fascia were infiltrated with a sparse mixture of lymphocytes and histiocytes. In the deep fascia, in addition to inflammatory cells, there were distinctive, reactive mesenchymal cells that showed features of both histiocytes and fibrocytes. Minimal tissue eosinophilia was seen despite the extent of blood eosinophilia. Dermal thickening and homogenization of collagen bundles occurred with replacement of fat and adnexa (changes indistinguishable from scleroderma or morphea). Vessel walls in the dermis and fascia showed thickening and endothelial swelling, but no overt vasculitis was noted. Skeletal muscle biopsies showed a perimysial, epimysial, and/or fascial inflammatory infiltrate of lymphocytes and distinctive reactive mesenchymal cells with some eosinophils. Minimal myofiber atrophy, regeneration, or necrosis was seen despite the clinical history of severe myalgias in almost all patients. This syndrome should help gain insight into the mechanisms of fibrosis in environmental-induced, scleroderma-like syndromes and in idiopathic, scleroderma-like disorders as well.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
EOSINOPHILIA-MYALGIA SYNDROME (L-TRYPTOPHAN INDUCED)
Eosinophilia-myalgia syndrome, eosinophilic fasciitis, and related fibrosing disorders. Varga J, Kahari VM. Section of Rheumatology, University of Illinois College of Medicine, Chicago 60607-7171, USA.	Curr Opin Rheumatol 1997 Nov;9(6):562-70 Abstract quote Clinically distinct fibrosing processes affecting the skin, selected internal organs, or both in a characteristic pattern are a common cause of morbidity. In addition to systemic sclerosis, the prototype idiopathic fibrosing disorder, these conditions include the eosinophilia-myalgia syndrome, epidemic toxic oil syndrome, eosinophilic fasciitis, localized forms of scleroderma, keloid, and the newly described entity of fibrosing colonopathy. The pathogenesis of these disorders, although still incompletely understood, appears to share similarities with that of systemic sclerosis. Insights into these diseases have recently emerged from epidemiologic and toxicoepidemiologic investigations, in situ hybridization and polymerase chain reaction amplification of target genomes, and in vivo and in vitro experimental research. Minor contaminants in food supplements, activation and degranulation of eosinophils, altered expression of CD34 antigen on dendritic cells, disordered regulation of fibroblast apoptosis and proliferation, infection with Borrelia organisms, and cytokines such as transforming growth factor-beta, interleukin-4, and connective tissue growth factor are implicated in inducing an accentuated and persistent fibrogenic host response to injury, resulting in tissue fibrosis. In addition, humoral and cellular autoimmunity may also be implicated.
TOXIC OIL SYNDROME
Toxic oil syndrome: the perspective after 20 years. Posada de la Paz M, Philen RM, Borda AI. Centro de Investigacion sobre el Sindrome del Aceite Toxico, Instituto de Salud Carlos III, Madrid, Spain.	Epidemiol Rev 2001;23(2):231-47 Abstract quote Toxic oil syndrome burst upon the scene in Spain in May of 1981, draining the resources of a newly evolving political and social medicine system. The vehicle of the causative toxic agent was identified as an illicit oil that had been diverted from industrial use and refined in order to remove the aniline denaturant, and that was sold in unlabeled 5-liter containers by itinerant salesmen. Over 20,000 people were ultimately affected, and over 1,200 deaths from all causes have been recorded in the affected cohort. The epidemiologic investigation of toxic oil syndrome involved all facets of investigative and analytical work; from visits to factories and interviewing workers, to sophisticated chemical and statistical analytical techniques. This investigation serves as a further illustration that data and information of all types, and from a wide range of fields, need to be systematically collected and evaluated in order to best resolve an epidemiologic mystery. Astute clinical observation of the patients, however, led to the hypothesis that toxic oil syndrome was a result of a toxic exposure. In this and other epidemics of unknown etiology, clinical observation and the intense scrutiny of patients' histories, signs, and symptoms by treating clinicians have often led to hypotheses that could be tested epidemiologically. When there are medical unknowns, the role of the astute clinician continues to be crucial. The toxic oil syndrome epidemic is an example of how even a developed country can be affected by a massive epidemic of environmental origin if failures occur in the systems that control and regulate the food supply or other consumer products. However, such failures could occur anywhere that large commercial networks operate on the regulatory edge, and if these business lack an in depth knowledge of the consequences of alterations in manufacturing conditions. Such was the case with eosinophilia-myalgia syndrome as well, when apparently minor alterations in manufacturing conditions of L-tryptophan led to an increase in impurities in the product that were later associated with the illness. These risks are even greater in countries with few or inconsistent control systems, making the food and drug supply potential portals of entry for serious health hazards, as is further exemplified by the tragic episode of pediatric renal failure in Haiti associated with a legitimate consumer product, paracetamol elixir, that had been manufactured using a fraudulently supplied toxic ingredient, diethylene glycol. The potential toxicants in the adulterated rapeseed oil were present in extremely small amounts. If fatty acid anilides or related compounds are indeed the etiologic agents in toxic oil syndrome, then these compounds must be extremely toxic at the parts per million concentrations at which they were found. Further, the roles of causative agents in the development of disorders such as scleroderma, eosinophilic fasciitis, eosinophilic perimyositis, and other similar diseases are unknown, but scientists can speculate that some sort of low level environmental agent may play a role if such extremely small quantities of contaminants are indeed capable of causing disease. Although the exact identity of the etiologic agent in toxic oil syndrome remains unknown, work on toxic oil syndrome continues. Follow-up clinical studies and long-term mortality studies are under way. Investigation of the mechanisms involved in toxic oil syndrome continues. The identification of suspect chemical compounds, their characterization, and effects will hopefully one day contribute to the prevention of other similar diseases.

 

PROGNOSIS

CHARACTERIZATION

 

TREATMENT	CHARACTERIZATION
GENERAL
SURGERY
Therapeutic fasciectomy for eosinophilic fasciitis. Neumeister MW, Robertson GA. Section of Plastic Surgery, Health Science Centre, Winnipeg, Manitoba, Canada.	Ann Plast Surg 1998 Aug;41(2):208-10 Abstract quote Eosinophilic fasciitis is an uncommon and potentially debilitating sclerodermalike connective tissue disorder. A patient is presented for whom medical and pharmacological management had failed to prevent the progression of forearm pain, fibrosis, and flexor contractures. Definitive management with forearm fasciectomy resolved the pain and contractures of the hand. Therapeutic fasciectomy may be a consideration earlier in the course of this disease to ameliorate its debilitating factors. The literature is reviewed.
TRANSPLANTATION, BONE MARROW
Successful treatment of severe Shulman's syndrome by allogeneic bone marrow transplantation. Cetkovsky P, Koza V, Cetkovska P, Svojgrova M. Department of Haematology and Oncology, Charles University Hospital, Pilsen (Plzen), Czech Republic.	Bone Marrow Transplant 1998 Mar;21(6):637-9 Abstract quote We describe a patient with severe Shulman's syndrome (ShS) (eosinophilic fasciitis). This auto-immune disease involved not only the skin and muscles, but the bone marrow as well - thereby fulfilling the criteria of severe aplastic anemia. As the disease was steroid-resistant, the patient underwent allogeneic bone marrow transplantation (BMT). Remission of ShS was achieved. Eight months later chronic GVHD developed and relapse of ShS (probably induced by GVHD) occurred. He was successfully treated with corticosteroids and the disappearance of GVHD was followed by cessation of the symptoms of ShS. At present (34 months following BMT) he is doing well and displays no signs of ShS or GVHD. This case suggests that an aggressive immunoablative preparative regimen with subsequent allogeneic BMT can result in long-lasting clinical remission of a severe auto-immune disease.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Got Path?
Recent teaching cases and lectures presented in conferences

• Pathologists Who Make A Difference
• Search for a Physician Specialist

Last Updated October 19, 2005

Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.

Copyright © The Doctor's Doctor