The fascia in systemic scleroderma

The fascia in systemic scleroderma Miguel Vazquez Botet, M.D.,* and Jorge L. Sanchez, M.D.

San Juan, Puerto Rico Diffuse fasciitis (DF) shares clinical and pathologic features with systemic (SS) and localized scleroderma. The distinct pathologic feature in DF is involvement of the deep fascia, but it is not known if these changes consistently' occur in SS. In this study, ten patients with SS underwent deep biopsies for evaluation of the fascia. All cases showed typical dermal histologic findings of scleroderma, and five cases showed thickening and fibrosis of the fascia. This study provides evidence that fascial involvement is not distinctive of OF but may occur in SS. It appears that thickening of the fascia is another morphologic feature shared between DF and SS. (J AM ACAD DERMATOL 3:36-42, 1980.)

In 1974, Shulman I described an apparently new syndrome in two men that was characterized by rapid onset after physical exertion, skin induration of the trunk and extremities without Raynaud's phenomenon or visceral involvement, and associated eosinophilia and hypergammaglobulinemia. Biopsy specimens did not show the typical sclerodermatous changes but showed a thickened fascia with a diffuse inflammatory cell infiltrate of lymphocytes and plasma cells. A striking feature was the improvement in response to steroid therapy. Since the pathologic findings were restricted to the deep fascia between the subcutaneous tissue and muscle, Shulman suggested the term "diffuse fasciitis (OF) with eosinophilia" for this new disease or syndrome. 1.2 Subsequently, many cases have been reported,:l-21 some showing differences either in clinical, pathologic, and/or laboratory characteristics to the original description. Rodnan et al" noted the presence of eosinophils in the involved From thc Section of Dermatology, Department of Medicine, Univcrsity of Puerto Rico School of Medicine. Reprint requests to: Dr. Miguel Vazquez Botet, Condominium Villas del Mar. Apt. 15 F-West. Isla Verde, Puerto Rico 00913. "Now Attending Physician with the Section of Dermatology. Department of Medicine. Caguas Regional Hospital. Caguas, Puerto Rico.

36

fascia and suggested the term "eosinophilic fasciitis." Other authors!l·IJ.,:; noted inflammation not only in the fascia but also in the dennis, subcutaneous tissue, and muscle. with dermal fibrosis and thickened interlobular septae similar to histopathologic findings seen in generalized morphea and systemic scleroderma (SS). Three patientsIO.I;;.IG have shown OF in association with internal manifestations and laboratory findings similar to those of SS. Jarrat, Bybee. and RamsdelF-t reported a case which presented clinically and histologically as eosinophilic fasciitis and later progressed over a 3-year period to SS. Based on their cases, Caperton, Hathaway, and Dehner'? called attention to the broad spectrum of disease existing between the entities of morphea. fasciitis, and scleroderma with eosinophilia. Fleischmajer et all:> concluded that' 'the clinical picture of DF is similar to generalized morphea" and that "the only distinct pathological feature in DF is the involvement of the deep fascia. " However. as they and other authors':' have pointed out. it is not known if the fascia is really involved in scleroderma due to lack of deep biopsies in most of the cases. The purpose of this study was to determine whether fascial involvement may be associated with SS. 0190-9622/80/070036+07500.70/0 © 1980 Am Acad Dcrrnatol

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Fascia ill systemic scleroderma

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Fig. 1. Control l. Normal-staining fascia consisting of loose connective tissue fibers between adipose and muscle tissue . Note the presence of blood vessels and fat cell s between the connective tissue fibers. (Hematoxylin-eosin stain ; original magnification, x 10.)

o

MATERIALS AND METHODS

Histology of controls

Ten patients with SS were selected for this study. There were nine women and a man, with ages ranging from 24 to 63 and the duration of the condition from 2 to 24 years (Table I). All of the patients had acrosclerosis , Raynaud's phenomenon, and involvement of at least one other organ system in addition to the skin. None of the patients were treated with corticosteroids nor exhibited blood eosinophilia (>400 eosinophils/mm)3.z:I at the time of biopsy. The lungs and the gastrointestinal tract were the two organs most frequently affected aside from the skin and joints. These were determined by clinical symptoms , chest x-rays, pulmonary function studies , and gastrointestinal radiologic studies, respectively. After informed consent, skin biopsies were performed by surgical excision from the more indurated areas, usually the external aspect of the forearms (except the hands), and included skin, subcutaneous tissue, fascia, and muscle. Tissues were fixed in buffered formaldehyde solution, embedded in paraffin. and sectioned and stained with hematoxylin and eosin in the routine fashion. Skin speci mens , including subcutaneous tissue, fascia, and muscle, were obtained from five cadavers (ages at death , 38 to 60) from forearms and taken as controls. None of them showed signs of scleroderma.

The epidermis appeared normal in all specimens. The dermis and subcutaneous tissue were normal except for basophilic degeneration of the connective tissue fibers in the upper dermis in three of the cases. In all five control specimens, the fascia appeared between the adipose and muscle tissue as loose, eosinophilic, horizontally oriented connective tissue fibers with normal-appearing fibrobla sts (Fig. I). Occasionally, adipose cells and small, thin-walled blood vessels were present within the connective tissue. Th e muscl e tissue fibers did not show any abnormalities.

Histology

0

The pathologic findings are summarized in Table II. The epidermis appeared normal in four patients, while six showed atrophy with effacement of the rete ridges. The pilosebaceous apparatus and sebaceous glands often were decreased in number, and, when present, most of them exhibited atrophic changes together with sclerosis of the surrounding connective tissue . Seven patient s showed clo sely packed eccrine sweat glands in the mid-dermis, surrounded by compact collagen with dilatation of the lumina and atrophic and degenerative changes of the cells. Sometimes in the same specimens, however, other nearby eccrine glands were normal in

38

Journal of the American Academy of Dermatology

Botet and Sell/chez

Table I. Clinical dat a Clinical picture

Sex

Age

UT)

Raynaud's ph enomenon

F

53

24

Presenl

Fac e , arms, hand s, legs

Arth ralgia , dyspn ea, dysphagia

2

F

45

6

Present

Fac e , arms , hand s , legs, chest

Arthralgia, he adaches , ho arse ness, dysph agia , skin ulce rs

3

F

51

8

Present

Face , arms, hands , legs

Arthralgi a , ca lcinosis, dy spn ea , hyperten sion, hepatome galy, sicca syndro me

4

F

63

20

Present

Face, arms, hands, legs, fe et

Arthralgia, dysphagia, skin ulc ers, thrombophlebitis

5

F

24

4

Present

Face , arms , hands, legs , ch est

Dy sph agia

12

Present

Fa ce, arm s, hands

Dysph agia

10

Present

Face , arms, hand s

Arthralgia, dyspn ea

13

Present

Face , arm s , hands , legs, chest , abdomen , feet

Arth ralgia , alopecia , cal cinosis , headaches , my algia , dy spnea, dysphagia, skin ulcers

Duration Patient

I

Acroscl erosis

I

Additional signs and symptoms

6

F

7

F

8

M

50 55 43

9

F

41

5

Present

Face , arms, hands, legs

Arthralgia

10

F

28

2

Present

Fa ce, arms, hands

Arthralgia

*The normal value is <400 cells per cubic millimeter." t Abnormal pulmonary function studies indicate either gas diffusion impairment and/or restrictive dysfunction.

Table II. Summary of histologic obser vations Dermis

Patient

2

I

Subcutaneous tissue

Biopsy site

Epidermis

Connective tissue

Forearm

Atrophic

Compact

Normal

Fibrillar and focally hyalinized

Arm

Atrophic

Compact

Atrophic

Hy alini zed and focally fibrill ar

Eccrine sweat glands

Connective tissue

3

Forearm

Normal

Fibrillar

Normal

Fib rill ar

4

Forearm

Normal

Fibrillar

Atrophic

Fib rill ar

5

Forearm

Atrophic

Compact

Normal

Hy alin ized

6

Forearm

Atrophic

Compact

Atrophic

Fibrillar

7

Forearm

Atrophic

Compact

Atrophic

Hyalinized

Atrophic

I

Fat

Reduced

8

Forearm

Normal

Compact

Hyalinized

Reduced

9

Leg

Norm al

Compact

Atrophic

Fibrillar

Reduced

Forearm

Atrophic

Compact

Atrophic

Hyalin ized

10

*Mild superficial perivascular Iymphohistiocytic cell infiltrate. tModerale superficial and mid-derm al lymphoh istlocytic cell infiltrate.

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Fascia ill systemic scleroderma 39

Laboratory data Xvray films

Blood eosinophils

%

I

Absolute"

7

0 0

Abnormal'[

Mild cardiomegaly

75

Esophageal dysmotility

Normal

Normal

Normal

Abnormal'[

Esophageal dysmotility

Fibrosis

Abnormal]

Esophageal dysmotility

Normal

Esophageal dysmotility

Normal

Normal

Normal

Abnormalt Abnormal!

260 294 261

3

Pulmonary function

Esophageal dysmotility

64

4

Chest

72

332

4

I

Gastrointestinal

Esophageal dysmotility

0 0

Normal

Normal

Abnormal'[

Normal

Abnormal'[

Muscle

Infiltrate

Thickened

Focal hyalinization

Mild sup. LH*

Normal

Focal hyalinization

Mild sup. LH*

Normal

Focal hyalinization

Mild sup. LH *

Normal

Not available

Mild sup . LH*

Thickened

Not available

Mod. sup. and mid -LHt

Thickened

Focal hyalinization

M ild sup. LH*

Normal

Focal hyalinization

Mild sup. LH *

Thickened

Focal hyalinization

Mild sup. LH*

Thickened

Normal

Mild sup. LH *

Normal

Normal

Mod. sup. and mid-LHt

ECG, right bundle branch block Weakly positive direct Coombs' test

Normal

Fascia

Other

Cryoglobulinemia

ECG , low volta ge and OLD septal scar

appearance and placed at the junction between the dermi s and the subcutaneous tissue . The connective tissue between the epidermis and the sweat glands was compact in almost all cases and consisted of large, thick, tightly packed collagen bundles which stained normally with hematoxylin and eosin (Fig . 2). In Patients 3 and 4, the connective tissue appe ared more fibrillar showing great variability in fibril thickness, with increased fibroblasts and with a few individual adipocytes within the dermis. In the area corresponding to the subcuta neo us tissue, all specimens showed thickening of the interlobular septae (Fig . 3), and in three cases the fat tissue was significa ntly replaced by connective tissue. The collagen in the subcutaneous tissue appeared in two forms. In some are as , a "hyalin" connective tissu e was seen as homogenous nonfibrillar masses which stained lightly with hematoxylin and eosin, while in other areas the connective tissue consisted of thin-pale loose bundles of fibrils (see Table II). A large numb er of fibrobla sts were noted within the area s of hyalinization . The vessels in the upper dermis were within normal limits . The small arterioles had a normal lumen and wall. The venules and lymphatics appeared normal. In

40 Botet and Sanche: .

lournal of the American Academy of Dermatology

Fig. 2. Case 2. Typical dermal histologic findings of scleroderma showing dense , compact, and sclerotic collagen fibers with almost total absence of epidermal appendages . (Hematoxylin-eosin stain; original magnification, X4 .)

..

Fig. 3. Case 2. Thickened interlobular septae showing hyalinized connective tissue fibers. The small artery shows thickening of the media and intima with reduction of its lumen. (Hematoxylin-eosin stain; original magnification, x4 .) the subcutaneous tissue, Patient 6 showed numerous clustered, small, thin-walled vessels in areas where connective tissue replaced the adipose tissue. In six ca ses, there were vascular changes involving the arterioles and small arteries , consisting of hyalinization and thickening of the intima and media, with reduction of their lumen. The fascia appeared normal in five patients. It con-

sistcd of normal-appearing, horizontally oriented connective tissue fibers between the adipose and muscle tissue. Patient 3, although normal in fascial thickness, showed focal areas where the connective tissue fibers appeared den se , compact, and sclerotic, a feature not seen in any of the control specimens . Five patients showed marked fascial thickening and fibrosis, having large, thick, pale, tightly packed collagen bundles

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Fascia ill systemic scleroderma

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)

Fig. 4. Ca se 8. Specimen showing a thickened fascia with sclerotic collagen and focal loss of cross-striations of the muscle tissue fibers . (Hematoxylin-eosin stain; original magnification, X 10.) throughout the width of the fascia, with increased normal-appearing fibroblasts (Fig. 4) . There was a lack of inflammatory cell infiltrate . In six of eight patients in whom the muscle was examined , focal areas of pale, homogenous muscle bundles were seen, with loss of their cross-striations. No other abnormalities were found. All patients were characterized by striking lack of inflammatory cell infiltrate in the subcutaneous tissue, fascia, and muscle. In eight of the patients, there was a superficial perivascular Iymphohistiocytic infiltrate, and in two patients there was a moderate superficial and mid-dermal infiltrate.

COMMENTS

Most of the histopathologic findings of this study are similar to others previously reported in SS.26- ;1O They essentially consisted of homogenization or hyalinization of the collagen fibers, some atrophy of the epidermis and its appendages, some reduction of fat with substitution by connective tissu e in the subcutaneous tissue , thickening and hyalinization of the arterioles and small arteries, focal hyalinization of muscle, and a notable lack of inflammatory cell infiltrate . The lack of infiltrate, especially at the reticular dermis and subcutaneous tissue found in this study, contrasts with another study"I in which 49% of the patients showed a significant perivas-

cular or diffuse mononuclear cell infiltrate ranging in duration of disease from se veral months to 20 years. However, the presence or severity of skin cellular infiltrates did not correlate with the duration of disease. In the present study, among ten patients with a duration of the condition between 5 and 24 years, eight showed only a spa rse superficial perivascular mononuclear cell infiltrate, while two patients showed a mild to moderate superficial and mid-dermal mononuclear cellular infiltrate . There have been several reports describing eosinophilia in association with SS . Fleischmajer et ap s noted blood eosinophilia in thirteen of sixty-seven patients with SS and also observed three or more eosinophils per high-power field in six of twenty SS biopsies . Our findings are similar to those of Shulman ," who could not find a single case associated with blood eo sinophilia, and to those of other histopathologic reports 26- 3 0 in which eo sinophils were not demonstrated in tissue infiltrates of SS. It is significant that none of our patients had been treated With systemic steroids, drugs that are well known for their eosinopenic effects . The present study was designed to examine the fascia in SS. All patients showed similar clinical skin findings consisting of diffuse, tight, indurated

42

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areas bound to the underlying tissues. In five of ten patients, the fascia was thickened, showing closely packed, thick and homogeneous connective tissue bundles with a notable lack of inflammatory cell infiltrate. It is known that in DF besides the inflammation, there is frequently thickening of the fascia as sometimes occurs in morphea, especially linear rnorphea.V!' where involvement of the underlying structures, such as the fascia and skeletal muscle, may occur. Just as in 55 the cellular infiltrate is less pronounced than in localized scleroderma,"! it may be possible that fascial inflammation in 55 is inconspicuous compared to DF, explaining the thickening of the fascia without inflammation found in this study. It would be interesting to know if similar histologic findings at the level of the fascia would be seen in DF after the acute inflammatory stage subsides. On the basis of this study, we conclude that fascial involvement is not a distinctive characteristic of DF but that thickening and fibrosis of. the fascia may also occur in 5S. We view that in some cases, the initial alteration in blood vessels:" may also occur in the blood vessels near the fascia, giving rise to collagen deposition and thickening of the fascia. It appears that thickening of the fascia is another morphologic feature shared between DF and 5S. REFERENCES I. Shulman LE: Diffuse fasciitis with hypcrgarnrnaglobulinernia and eosinophilia: A new syndrome. J Rheumatol l(suppl 1):46, 1974. 2. Shulman LE: Diffuse fasciitis with eosinophilia: A new syndrome? Trans Assoc Am Physicians 88:70-86, 1975. 3. Rodnan GP, DiBartolomeo AG, Mcdsgcr TA Jr, et al: Eosinophilic fasciitis: Report of six cases of a newly recognized scleroderma-like syndrome. Arthritis Rheum 18:525, 1975. 4. Caperton EM, Hathaway DE: Scleroderma with eosinophilia and hypergarnrnaglobulincrnia: The Shulman syndrome. Arthritis Rheum 18:391, 1975. 5. Schumacher HR: A scleroderma-like syndrome with fasciitis, myositis and eosinophilia. Ann Intern Med 84:49-50, 1976. 6. Gray RG, Poppo MJ: Eosinophilic fasciitis: A scleroderma-like illness. JAMA 237:529-530, 1977. 7. Talbott IN, Cusani BA: Fasciitis (eosinophilic) with scleroderma-like changes in the skin. J Fla Med Assoc 63:702-705, 1976. 8. Camus JP, Crouzet J, Prier A: Shulman's syndrome (pseudoscleroderma with eosinophilia): Two cases and review of the literature. Ann Intern Med 127:491-495, 1976. 9. Ansell BM, Nassen GA, Bywaters EGL: Scleroderma in

Journal of the American Academy of Dermatology

childhood. Ann Rheum Dis 35: 189-197, 1976. 10. Caperton E~L Hathaway DE, Dehner LP: Morphea fasciitis and scleroderma with eosinophilia: A broad spectrum of disease. Arthritis Rheum 19:792-793, 1976. II. Krauser RE, Tuthill RJ: Eosinophilic fasciitis. Arch Dcrrnatol 113:1092-1093, 1977. 12. Torres VM. George WM: Diffuse eosinophilic fasciitis. Arch Dermatol 113:1591-1593. 1977. 13. Shewmake SW, Lopez DA, McGlnmory JC: The Shulman syndrome. Arch Dcrmatol 114:556-559, 1978. 14. Weinstein D, Schwartz RA: Eosinophilic fasciitis. Arch Dcrmatol 114:1047-1049, 1978. 15. Flcischmajer R, Jacotot AB. Shore S. Binnick SA: Scleroderma, eosinophilia. and diffuse fasciitis. Arch Dcrrnatol 114:1320-1325, 1978. 16. Chanda JJ, Callen JP, Taylor WB: Diffuse fasciitis with eosinophilia. Arch Dermatol 114:1522-1524, 1978. 17. Lupton GP, Goette DK: Localized eosinophilic fasciitis. Arch Dcrmatol 115:85-87, 1979. 18. Hoffman R. Dainiak N, Sibrack L. Pober JS, Waldron JA: Antibody-mediated aplastic anemia and diffuse fasciitis. N Engl J Med 300:718-721, 1979. 19. Stubbs SL, Hughes GRE: Eosinophilic fasciitis. Br Med J 1:948-949, 1977. 20. Kanard RR: Eosinophilic fasciitis. Rocky Mt Med J 74: 186-188, 1977. 21. Bennet RM, Herron A, Keogh L: Eosinophilic fasciitis: Case report and review of the literature. Ann Rheum Dis 36:354-359, 1977. 22. Lewis RB. van Valkenburg WD: Eosinophilic fasciitis, Ann Intern Med 88:577-578, 1978. 23. Fu TS, Soltani K, Sorensen LB, Levinson D, Lorincz AL: Eosinophilic fasciitis. JAMA 240:451-453, 1978. 24. Jarratt M, Bybee JD. Ramsdell W: Eosinophilic fasciitis: An early variant of scleroderma. J A~l ACAD DER~tATOL 1:221-226, 1979. 25. Miale JB: Laboratory medicine: Hematology, ed. 5. SI. Louis, 1977, The C. V. Mosby ce.. p. 774. 26. O'Leary PA. Montgomery H, Ragsdale WE: Dermatohistology of various types of scleroderma. Arch Dermatol 75:78-87, 1957. 27. Fisher ER, Rodnan GP: Pathologic observations concerning the cutaneous lesion of progressive systemic sclerosis: An electron microscopic, histochemical and immunohistochemical study. Arthritis Rheum 3:536-545, 1960. 28. D'Angelo \VA, Fries JF, Masi A, et al: Pathologic observations in systemic sclerosis (scleroderma). Am J Med 46:428-440, 1969. 29. Winkelmann RK: Classification and pathogenesis of scleroderma. Mayo Clin Proc 46:83-91, 1971. 30. Fleischmajer R, Damiano V, Nedwich A: Alteration of subcutaneous tissue in systemic scleroderma. Arch Derrnatol 105:59-66, 1972. 3 I. Fleischrnajer R, Perlish JS, Reeves JRT: Cellular infiltrates in scleroderma skin. Arthritis Rheum 20:975984, 1977. 32. Christianson HB, Dorsey CS, O'Leary PA, et al: Localized scleroderma. Arch Dermatol 74:629-639, 1956. 33. Dilley 11, Perry HO: Bilateral linear scleroderma en coup de sabre. Arch Dcrrnatol 97:688-689, 1968. 34. Fleischrnajer R: The pathophysiology of scleroderma. Int J Dermatol 16:310-318, 1977.