The pathology and pathogenesis of malignant atrophic papulosis (Degos' disease)

Path. Res. Pract. 182,98-106 (1987)

The Pathology and Pathogenesis of Malignant Atrophic Papulosis (Degos' Disease) A Case Study with Reference to other Vascular Disorders W. M. Molenaar Department of Pathology, University of Groningen

J. 8. Rosman Department of Medicine, University of Groningen

A. J. M. Donker Department of Medicine, University of Groningen (present address: Dept. of Medicine, Hospital of the Free University of Amsterdam)

H. J'. Houthoff Department of Pathology, University of Groningen, present address: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands

SUMMARY

The morphology and immunohistology in a case of malignant atrophic papulosis (Degos' disease), a rare vascular disorder of unknown etiology, are described. The vascular lesions affected middle class and small arteries and veins throughout the body and were histologically characterized by intimal proliferation in the absence of any appreciable inflammation. The lesions were categorized as early, intermediate or late. Early lesions consisted of cellular proliferation and edema of the intima with signs of immune complex deposition (IgM, e3). Thombosis was occasionally present as a secondary phenomenon in the affected vessel segments. In intermediate lesions the edema decreased and smooth muscle proliferation became apparent. Late lesions consisted of acellular intimal sclerosis with hyalinization and narrowing or obliteration of the vascular lumen. The media of the vessels remained always intact. In comparing these features to the pathology and pathogenesis of other vascular disorders they resembled the vascular lesions in a murine model of lupus erythematodes in which also considerable intimal proliferation occurred with thrombotic occlusion, but without appreciable inflammation. The murine .model is associated with sustained low levels of circulating immune complexes and it is tempting to assume the same for Degos' disease. The notion of an immune complex mediated non-inflammatory condition underlying ihis severe and often fatal vascular disorder of mainly young males may contribute to the eventual finding of a successful therapeutical regimen. 0344-0338/87/0182-0098$3.5010

© 1987 by Gustav Fischer Verlag, Stuttgart

Malignant Atrophic Papulosis . 99

Introduction Malignant atrophic papulosis (MAP) or (Kohlmeier-) Degos' disease is a rare vascular lesion occurrin gredominantly in males, especially in early adult life 2,6, , 5, 19. It involves hoth .arteries and veins throughout the body and gives rise to characteristic skin lesions. The latter usually are the presenting feature, but may become manifest simultaneously with or even after the onset of systemic symptoms 6, 16. We recently reported a case in which no skin lesions were clinically apparent, but which was otherwise characteristic of the disease including the histopathology of the skin l8 . In the present paper the morphology and immunohistology of the vascular lesions are described more in detail and an attempt was made to gain more insight in the pathogenetic and etiologic factors. Histologically, the essential vascular lesion of MAP consists of intimal rroliferation in the absence of vascular inflammation2,4, ,9. The absence of an inflammatory component clearly distinguishes the disease from many types of vasculitis, such as a Buergers disease, Wegeners granulomatosis, necrotising vasculitis including polyarteritis nodosa, and allergic vasculitis. On the other hand, there are morphologic similarities of MAP with isolated fibromuscular dysplasia of the renal arterylO, 11, with obliterating endarteritis5 and with a recently described murine model of degenerative vascular disease related to systemic lupus erythematodes l . Specimens of these conditions were therefore included in the study as reference material. The vascular lesions were studied with histological and immunohistochemical methods to describe the pathology of this rare disease and to elucidate the possible pathogenetic mechanisms and etiologic factors.

9

Case history A 17 -year-old male patient was admitted to the hospital with complaints of severe abdominal pain and convulsions. The past history was uneventful apart from heroin use up to 5 months before. At physical examination the patient appeared cachectic and his sclerae were slightly icteric. The liver was 4 cm's palpable. His temperature was 37.rC, his pulse rate 100/min and blood pressure 1701120 mmHg. Laboratory findings showed liver.. and kidney function disturbances and sera positivity for HBsAg. An upper gastrointestinal X-ray was normal. A diagnosis of neglect and dehydration was made, possibly due to hepatitis B infection and symptomatic treatment was given. The gastro-intestinal symptoms improved slightly and the blood pressure normalized to 120170 mmHg, but the temperature rose to 38.1°C and convulsions recurred. In addition, the patient developed diplopia, pain in the back, coughing and orthopnoea with radiographically patchy infiltrates in both lungs. Despite corticosteroid and antibiotic treatment the pulmonary situation deteriorated and artificial respiration became necessary. The renal failure also aggravated and haemodialysis was begun. In the meantime progressive ischaemic changes had developed in the right leg, which appeared to be due to complete occlusion of the right common and external iliac arteries and the popliteal artery. A lower leg amputation had to be performed. Renal arteriography revealed irregular contours of smaller vessels with multiple infarctions bilaterally. Under the diagnosis of "vasculitis" the patient was

treated with cyclophosphamide with minimal success. Two months after admission he died of uncontrollable gastrointestinal bleeding. The material that was available for histological examination consisted of a skin biopsy from the dorsum of the right foot, the amputation specimen of the right lower leg, a skin-muscle-fascia biopsy, a temporal artery biopsy and finally the post-mortem material. All pathologic findings could be led back to vascular disease thoughout the body. These lesions included thrombosis in both atria and ventricles of the heart, in the jugular and subclavian veins and the inferior caval vein, as well as in the right common iliac and the right vertebral arteries. Small or large infarctions were found in the heart, lungs, kidneys, liver and spleen and the right lower leg was gangrenous. No ulcerations or infarctions were seen in the intestine, but bleeding was evident and vascular lesions were found microscopically. In the same way, no skin lesions were observed clinically or at postmortem but characteristic lesions were seen microscopically (see Results).

Control Material a) Isolated fibromuscular dysplasia of the renal artery A 36-year-old male patient presented with hypertension and because of abnormalities on the intravenous pyelogram and the arteriogram a nephrectomy was performed. The specimen showed a narrowing of the inferior segmental renal artery.

b) Obliterating endarteritis An example of this aspecific, presumably reactive, vascular lesion was found in a case of infiltrative gastric carcinoma with perineural extension and lymphogenic metastases.

c) Murine vasculitis A degenerative vascular lesion has been described in male (NZW x BXSB)F1 mice, which presumably is related to systemic lupus erythematodes 1• Dr. Berden has kindly provided paraffin blocks to use for comparison in the present study.

Methods Light microscopy Representative paraffin sections were stained with H& E, Verhoeff's elastin, phosphotungstic-acid-haematoxylin (PTAH) and toluidine blue as well as with combined Periodic acid-Schiff and Alcian Blue stains (pH 1 and 2.5) and with high irondiamine (HID) stains.

Immunohistology Immunofluorescence studies were performed on frozen sections of the skin biopsies and of the autopsy material from the kidney, using FITC-Iabeled antibodies to immunoglobulins (IgG, M, A; Kallestad, Austin TX, U.S.A.) and to complement (C3; Kallestad). The same material was studied using as a first step unlabeled rabbit antibodies to fibrin and its degradation products and monomeres (Central Laboratory of the Blood Bank; Amsterdam, The Netherlands), to coagulation factor VIII (Dako; Copenhagen, Denmark), and to fibronectin (Cappell; Cochranville, PA, U.S.A. ) followed by FITC-Iabeled goat anti rabbit Ig. The presence of hepatitis B virus surface- (HBsAg) and core

100 . W. M. Molenaar,

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Fig. 1. Histology. A-D: Degos' disease; (A) Focal atrophy of epidermis with hyperkeratosis in biopsy from the dorsum of the foot (H & E, x 180); (B) Early vascular lesion with thrombosis in the same specimen (H & E, x 140). (C) Intermediate vascular lesion in kidney at post mortem (PAS-Alcian Blue, x 140); (D) late lesion in kidney at postmortem (PAS-Alcian Blue, x 180); (E) Fibromuscular dysplasia of renal artery (Verhoeff's elastin stain, x 56); (F) Murine degenerative vascular disease in small intestine. Arrows: early changes with deposition of PAS-positive material in small vessel. Asterisks: infarced mucosa (PAS, x 140).

Fig. 1. D-E

Fig. 2. A-C

Fig. 2. Immunofluorescence of Degos' disease. A-D skin-muscle-fascia biopsy. (A) C3 depositions in relatively early vascular lesion (x 25); (B) Absence of C3 depositions in older lesion in the same specimen (x 10); (C) Endothelial positivity for factor VIII in affected blood vessel (x 10); (D) Depositions of IgM in intima (x 10); E-F, kidney at postmortem; (E) Presence of fibrin monomeres in glomerular thrombus (x 10); (F) Absence of IgG deposition in affected renal artery at postmortem (x 10).

Fig. 2. D-F

104 . W. M. Molenaar,

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(HBcAg) antigens was studied in frozen sections of the skin and kidney using peroxidase conjugated antibodies (Organon, Oss, The Netherlands), as previously described I2 •

J.

Houthoff Table 1. Pathology in early, intermediate and late vascular lesions of Degos' disease: results early

Results

Histology

Light microscopy

PAS diastase Alcian Blue

PTAH

a) Degos' disease

HID

Microscopically, the skin showed vascular lesions accompanied by focal epidermal atrophy, hyperkeratosis and papillomatosis (Fig. lA). The vascular lesions in the skin and other organs consisted of intimal proliferation with consequent (partial) occlusion of the vascular lumen. In addition, focal thrombosis was found .(Fig. lB), in some places showing recanalization. Apart from a mild inflammatory infiltrate in the first skin biopsy, an inflammatory component was consistently absent. Moreover, elastin stains revealed an intact internal and external elastic lamina, which practically excludes a healed vasculitis. In the H & E stained sections various stages in the vascular lesions could be recognized. It was assumed that edematous, cellular intima proliferation represented the earlier stage of the disease (Fig. lB) and a dense, amorphous, thick intima the final stage (Fig. lD). In intermediate stages the edema decreased and smooth muscle proliferation became more apparent (Fig. 1 C). Thrombosis seemed to be a secondary phenomenon and occurred predominantly in earlier lesions: The mucin stains showed a variable positivity (Table 1), such that the PAS-stain tended to be positive in intermediate lesions and the AB-stains in early lesions. No positive staining was found in end-stage lesions. The PTAH-stain revealed smooth muscle cell proliferation especially in relatively old lesions with extensive intimal thickening. HID-stains were consistently negative. ..

b) Fibromuscular dysplasia of the renal artery The microscopical picture of this renal artery branch showed extensive intimal proliferation with occlusion and recanalization of the lumen and intact elastic lamina (Fig. lE), comparable to an end-stage lesion as suggested above. The PTAH-stain as well as the mucin stains were negative. It is of interest, however, that some AB-positivity was observed in a seemingly normal arterial branch of the same kidney.

c) Obliterating endarteritis Microscopically, similar vascular changes were observed as in Degos' disease, except thrombosis. In the same way various stages in the development of the lesions were observed with comparable staining properties.

d) Murine vasculitis (for details: ref. 1) The vascular lesions showed remarkable similarities to Degos' disease, including the deposition of PAS-positive material in early lesions; the absence of an inflammatory infiltrate and thrombotic occlusions (Fig. iF).

Immunohistology Ig (1) C3 (1) FM, Fdp (2) factor VIII (3) fibronectin HBsAglHBcAg

±

+

intermediate

late

+

++

+

+

+ ±

M

+ ±

+

(1) positive in dermal, not in renal vessels (2) only in some thrombi, variable in intima (3) only positive in areas with normal endothelial cells or after recanalisation

Immunohistology (Table 1) Some depositions of C3 and of IgM but not of IgG or IgA were observed in the intima of dermal vessels with early lesions (Fig. 2A, B, D, F). Fibrin monomeres appeared to be present in small thrombi (Fig. 2E), whereas fibrinogen, fibrin degradation products and fibronectin could not be demonstrated. Factor VIII stained endothelial cells of normal and affected vessels (Fig. 2C) including recanalized lumina. Hepatitis B surface and core antigens could not be demonstrated in either the skin or the kidney.

Discussion Malignant atrophic papulosis (MAP; Degos' disease) is a relatively rare disease of uncertain etiology and pathogenesis, which occurs predominantly in young males and is therapy resistant and often fatal 2 , 6, 7, 15,19. The clinical symptoms include non-painful, non-itching multiple infarcts of the skin and internal organs, although the former may be a late phenomenon or only microscopically evident as in the present case 6, 16, 18. If the typical skin lesions are absent, the clinical diagnosis of MAP is difficult, especially as it is only adequately described in the dermatologic literature, and the final diagnosis is commonly established by exclusion of other possibilities or only at autopsy. Histologically, the main features of MAP are: (a) involvement of both arteries and veins of small to medium size, (b) intimal proliferation in the absence of any appreciable inflammatory or necrotizing reaction, and (c) absence of any pathology in the tunica elastica, media or adventitia. The last two features differentiate MAP from allergic or necrotizing vasculitis, including polyarteriitis nodosa and from various types of thromboangiitis and Wegener's granulomatosis. In the present patient, a young male HBsAg seropositive homosexual heroin user, the

Malignant Atrophic Papulosis . 105 clinical picture predisposed for and mimicked a necrotizing vasculitis such as polyarteriitis nodosa. However, both the therapy resistance and the histologic features excluded this diagnosis. As the etiology and pathogenesis of MAP are essentially unknown 2, 6: 14, we considered as possible pathogenetic mechanisms (a) an intimal lesion with smooth muscle cell proliferation, (b) a primary lesion in the vasa vasorum or adventitia resulting in dystrophic intimal changes, (c) primary changes in the circulation, such as blood pressure changes or abnormal serum factors and (d) a primary endothelial lesion resulting in increased permeability and secondary thrombosis. The sequence of vascular changes with cellular proliferation and edema in early lesions and progressive intimal hyalinisation in older lesions were used as an indication of the involved mechanisms. In the early lesions the proliferating cells appeared not to be of endothelial or smooth muscle origin (no demonstrable factor VIII or PTAH-positivity), which makes a primary intimal lesion unlikely. The absence of changes in the adventitia and the vasa vasorum exclude a mechanism as suggested under (b). No evidence could be found to support a primary change in the circulation. Thus, serologic tests revealed no signs of circulating immune complexes, of rheumatoid arthritis or of an active viral infection. Moreover, hepatitis B antigens could not be demonstrated in the lesions. There were no signs of an (acquired) immune deficiency syndrome. The blood pressure remained within normal limits till an advanced stage of the disease. Finally, a primary endothelial lesion with increased endothelial permeability should be considered. It is supported by the intimal edema in early lesions, followed by smooth muscle cell proliferation, intimal hyalinisation and sclerosis, and prominent thrombosis due to the endothelial damage. A primary endothelial lesion may thus well be the primary event in MAP and is keeping with earlier electron microscopic 6, 13 and enzyme~histochemical findings 4 which indicate degenerative endothelial alterations. As for pathogenetic mechanisms, several etiologic factors for MAP may be hypothesized (for review cf.2,6), including an autoimmune mechanism, a secondary immune reaction, a viral infection or a metabolic disease. In this respect, it is of importance that in the early lesions the deposition of IgM and C3 could be demonstrated. Although IgM and C3 may be present in vascular lesions as a secondary, non specific entrapment, their exclusive presence in early lesions, makes the deposition of immune complexes and thus an immune mechanism as the etiologic factor more likely. The finding of immunoglobulin depositions exclusively in early lesions may also explain that several authors did not demonstrate such depositions 6 , whereas others did 17 • Vascular diseases characterized by intimal proliferation leading to vascular occlusion in the absence of an inflammatory or necrotizing reaction include, apart from MAP, also fibromuscul ar dysplasia of a renal artery, obliterating endarteriitis, and a recently described murine model o(degenerative vascular lesions in systemic lupus erythematodes 1. Of these, the murine model resembles MAP most, according to the morphology

Table 2. Comparison of the morphology of vascular lesions in Degos' disease (MAP), endarteritis obliterans (EO), fibromuscular dysplasia (FD) and murine SLE with degenerative vascular disease (DVD). SMC: smooth muscle cell. MAP EO

endothelial cells: proliferation degeneration intima: cellular proliferation homogenous deposits fibrous thickening media: SMC proliferation SMC degeneration perivascular inflammation

+

FD

+/+ +

+ + +

± + ++

± ±

± ± ±

DVD

+

+ ++ ±

± ±

and distribution of the lesions (see Table 2). As in MAP it occurs in male mice, has an early onset, and is characterized by disseminated non-inflammatory and degenerative vascular pathology with prominent secondary thrombosis. In this model a relation to SLE has been established, which has also been suggested for MAp3, 8. The murine model is associated with prolonged low levels of circulating immune complexes, probably deposited in the vessel wall in such a way that they do not exceed a certain threshold necessary to elicit an inflammatory response. A similar phenomenon may occur in patients with MAP. As for the current patient a renewed search for low levels of circulating immune complexes could no longer be performed and could not be excluded on the basis of the serologic data available. In conclusion, in the current case of Degas' disease without clinically manifest skin lesions, the pathology of the vascular lesions contributed appreciably in establishing this clinically difficult diagnosis. The current pathological findings which resemble those in a murine SLE model suggest that it consists of focal endothelial damage, with an indication of immune complex deposition in the early lesions as the eliciting factor. The notion of an immune complex mediated non-inflammatory condition, underlying this severe and often fatal vascular disorder may contribute to the use of new diagnostic parameters and the eventual finding of a successful therapeutical regimen. Acknowledgements The authors are grateful to Dr. J. c. v. d. Griendt for his examination of the first biopsy, to Mrs. D. v. d. Top for her technical help, to Mr. Wieringa for his photographic contributions and to Mrs. G. H. Bartels-Struik for typing the manuscript. References 1 Berden JHM, McConahey PJ, Dixon FJ (1983) Analysis of vascular lesions in murine SLE. 1. Association with serologic abnormalities. J Immunol130: 1699-1705

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2 Black MM (1976) Malignant atrophic papulosis (Degos' disease). Int J Dermatol15: 405-411 3 Black MM, Hudson PM (1976) Atrophie blache closely resembling malignant atrophic pap ulosis (Degos' disease) in systemic lupus erythematosus. Br J Dermatol 95: 649-652 4 Black MM, Nishioka K, Levene GM (1973) The role of dermal blood vessels in the pathogenesis of malignant atrophic papulosis (Degos' disease). A study of two cases using enzymehistochemical, fibrinolytic, electron microscopical and immunological techniques. Brit J Dermatol 88: 213-219 5 Crawford T (1976) In- Systemic Pathology, vol. 1, second edition. W Stc. Symmers (Ed), Churchill Livingstone, Edinburgh, London, New York 6 Degos R (1979) Malignant atrophic papulosis. Br J Dermatol 100: 21-35 7 Degos R, Delort J, Tricot R (1942) Dermatite papulosquameuse atrophiante (et epilogue). Bull Soc Fr Dermatol Syph 49: 148-150 8 Dubin HV, Stawiski MA (1974) Systemic lupus erythematosus resembling malignant atrophic papulosis. Arch Int Med 134: 321-323 9 Feuermann EJ, Dolberg L, Salvador 0 (1970) Malignant atrophic papulosis with mucin in the dermis. A clinical and pathologic study, including autopsy. Arch Pathol 90: 310-315 10 Harrison EG, McCormack LJ (1971) Pathologic classification of renal artesial disease in renovascular hypertension. Mayo Clin Proc

11 Hepinstall RH (1983) Pathology of the kidney. Little, Brown and Co, BostonfToronto 12 Houthoff HJ, Niermeijer P, Gips CH, Arends A, Hofstee N, van Guldener M (1980) Hepatic morphologic findings and viral antigens in acute hepatitis B. Virch Arch A 389: 153-160 13 Howard RO, Nishida S (1969) A case of Degos' disease with electron microscopic findings. Transact Am Ac Ophthalmol Otolaryng 73: 1097-1112 14 Howsden SM, Hodge SJ, Herndon JH, Freeman RG (1976) Malignant atrophic papulosis of Degos. Report of a patient who failed to respond to fibrinolytic therapy. Arch Dermatol 112: 1582-1588 15 Kohlmeier W (1941) Multiple Hautnekrosen bei Thromboangiitis obliterans. Arch Dermatol Syph 181: 783-792 16 McFarland HR, Wood WG, Drowns BV, Meneses ACO (1978) Pap ulosis atrophicans maligna (Kohlmeier-Degos disease): a disseminated occlusive vasculopathy. Ann Neurol 388-392 17 Repay VI (1969) Uber das Krankheitsbild, Papulose atrophiante maligne Degos. Dermatol Wochenschr. 155: 325 18 Rosman JB, Molenaar WW, Schuur KH, Hylkema BS, Houthoff HJ, Donker AJM (1984) A 17-year old HBsAg seropositive heroin user with generalized vascular disease. Neth J Med 27: 50-58 19 Strole WE, Clark WH, Isselbacher K (1967) Progressive arterial occlusive disease (Kohlmeier-Degos): a frequently fetal cutaneosystemic disorder. New Engl J Med 276: 195-201

Received January 14, 1986 . Accepted in revised form July 11, 1986

Key words: Degas' disease - Malignant atrophic papulosis - Immune complex vasculitis - Murine vasculitis Dr. W. M. Molenaar, Dept. of Pathology, University of Groningen, Oostersingel 63, 9713 EZ Groningen, The Netherlands