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Malignant Atrophic Papulosis Support Network WebsiteKöhlmeier-Degos Disease: An overview

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This paper is mainly intended to inform patients. Medical terms are explained in brackets so that patients who wish to learn these concepts can do so, in order (for example) to understand doctors’ reports and scientific literature.

Introduction

The Papulosis atrophicans maligna (Köhlmeier-Degos disease) is a very rare illness. It was described for the first time by Köhlmeier in 1941 and documented as a distinct illness by Degos in the same year. Since then about 130 cases have been written up in scientific literature.

Clinical picture

The characteristic skin changes of the Papulosis atrophicans maligna allow conclusive diagnosis. They begin as small erythematous (red) moles, commonly around the trunk and the upper extremities. After a few days the center of the lesion falls in, so older lesions show a porcelain-white atrophic (dead, sunk) centre with an erythematous (red) halo (outer ring)4. Characteristically it leaves the Palmae, Plantae, Capillitium and the Facies (face) untouched.

Age at which symptoms appear, family history

Symptoms normally appear between the age of 20 and 50. The illness usually occurs sporadically but on rare occasions it has affected several members of the same family.
Diagnostic criteria

Diagnosis of the Papulosis atrophicans maligna is usually decided clinically on the basis of the characteristic skin changes, and confirmed by histological (microscopic) examination. The laboratory tests are not by themselves conclusive, as coagulating disturbances may be present (see Etiology below).

Histology (Tissue Type)

Histologically the skin lesions typically show a wedge-shaped area of cutaneous ischaemie. The characteristic histological features with wedge-shaped tissue necrosis and thrombosis of the supplying blood vessels are not evident in all cases27. In one case report, Harvell examined the histology of the lesions in connection with their duration and postulated that early lesions can more closely resemble a Lupus of erythematodes due to their extended Muzin (deposits) in the dermis, and superficial as well as deep perivascular inflammation. Older lesions, on the other hand, bore more similarities to a minimal variant of the Lichen sclerosus et atrophicans, with their papillaere dermal sklerosis with Atrophie and Hyperkeratose28.

Etiology (Causes) of the illness:

The etiology (cause) of the illness is not yet known, and amongst other things genetic factors (transmission), auto-immunological processes (the immune system attacks its own body), an allergic vasculitis (blood vessel inflammation), an infectious agent (for example viruses or bacteria) and coagulopathiens (blood coagulation problems) have been proposed. There is a whole list of hypotheses, but none of them have yet been proven. A genetic predisposition has been suggested because cases of the Papulosis atrophicans maligna affecting several members of the same family are known. Within these families often members related in the first degree are affected, suggesting an autosomal dominant factor transmission151617.

Electron-microscopic evidence of intrazytoplasmatic paramyxovirus-similar inclusions has suggested an infectious etiology2130. Tests for paramyxovirus DNA from skin samples of patients with Papulosis atrophicans maligna by means of PCR gave negative results31. The crucial question must be whether the obliteration of the blood vessels in the affected skin areas results from a thrombosis in the context of a primary coagulopathy or whether it occurs as a consequence of a primary vasculopathy e.g. by release of tissue-active factors within the range of endothelium defects. There are no conclusive laboratory findings regarding the Papulosis atrophicans maligna. However, there are a relatively large number of reports of cases of patients with defects of the blood clotting system.

Drucker reports on a patient with increased thrombozyten aggregation on Adenosindiphosphat, Epinephrin, kollagen, Serotonin and Thrombin32. An increased thrombozyten aggregation has been recorded in other cases as well23.

Patients with Papulosis atrophicans maligna can exhibit the anticardiolipin antibodies and Lupus anticoagulans antibodies that accompany an increased thrombosis tendancy/susceptability1213. Also a lowered Fibrinolyse could be a cause of the capillary thrombosis in the lesions of the Papulosis atrophicans maligna. Black and others observed a complete loss of the fibrinolytic activity in the centres of the skin lesions and a reduction of the fibrinolytic activity in the peripheral blood11. With some patients an increased fibrinogen level was found2526. A degraded plasminogen level as well as increased activity of the plasminogen-activator inhibitors has also been documented in the context of the Papulosis atrophicans maligna21. There is (to date) one report of Papulosis atrophicans maligna in an HIV-infected homosexual man14.

Progression of the illness

The characteristic cutaneous (at the skin) efflorescences in most cases appear before the systemic (more than one organ is affected) effects of the disease occur. The illness can stay limited to the skin for many years, but if a systemic development occurs, close-knit medical control is needed, because serious problems can occur. Symptoms can result from ischemic complications (oxygen deficiency in the tissue caused by capillary blockages), where all organs can be affected, but the most serious aspects of the illness progression are above all intestinal (stomach and intestine) and central nervous system (brain) complications10.

The malignancy of the illness is shown by the fact that even after many years of purely cutaneous infection a systemic development can occur. The systemic manifestation can in many cases lead to grave complications after just a few months.

The most frequent serious complications are, in descending order, Peritonitis (inflammation of the abdominal linings), ZNS complications, pleurisy (inflammation of the lung membrane) and/or pericarditis (heart inflammation)10. The intestinal complications mainly affect the small intestine, with peritonitis frequently following an intestine perforation (intestine tear). Symptoms can be absent or be non-specific with abdominal pain, digestion problems etc. Neurological complications reported to date are consequences of cerebral vasculopathy (degeneration of the cerebral blood vessels) eg aspetic meningitis (non-bacterial inflammation of the brain membrane), enzephalitis (brain inflammation), radiculoneuritis (= nerve inflammation) and myelitis (backbone marrow inflammation)21. Implications for the eyes are rare, but can primarily involve the eyelids, the conjunctive (outer surface of the eye), retina and choroidea (blood vessel linings), and secondarily be neurological problems such as diplopy (double vision) and ophthalmoplegy (paralysis of the eye muscles).

Hypothesis: Do two forms of the illness exist? The malign and the benign forms?

Some patients may for many years, perhaps even lifelong, exhibit purely the cutaneous aspects of the disease. Many of these cases occur in families amongst relatives of the first degree. Cases of this at least in the long-term view “benign” effect are possibly not adequately documented, given that only lifelong observation of such patients can lead to a final evaluation of the seriousness of their illness. As a result it has not to date been clarified whether, alongside the serious “malignant” atrophic papulosis there is also a mild variant of the illness with purely cutaneous implications, and whether these two forms can clearly be differentiated from each other.

Treatment

There is as yet no proven-effective treatment of the Koehlmeier Degos disease. Immunosuppressive therapy trials with, for example, cyclosporin A, azathioprin, cyclophosphamide and steroids show no significant success. Treatments aimed at achieving anti-coagulative (restraining coagulation) and perfusion-promoting (improving blood circulation) effects have in some cases produced a lessening of the skin symptoms and/or had morbostatic effects (delaying the progression of the illness), and this applies particularly to acetylsalicylic acid (ASS), and also to Dipyridamol, Ticlopidin and Heparin.

Vicktor et al. report for the first time on the successful treatment of a patient with the cutaneous form of the illness with Pentoxyfyllin 1200 mg/die p.o. and ASS 100 mg/die p.o., producing an almost complete retreat of the skin lesions5.

References:

1 Köhlmeier W. (1941). Multiple Hautnekrosen bei Thrombangitis obliterans. Arch. Dermatol. Syph. 181, 783-792

2 Degos R., J. Delort, R. Tricot (1942). Dermatite papulosqameuse atrophiante. Bull. Soc. Fr. Derm. Syph. 49, 148-150

3 Snow J. L., S.A. Muller (1995). Degos Syndrome: malignant atrophic papulosis. Semin. Dermatol. 14, 99-105

4 Vazquez- Doval F.J., F.R. De Erenchun, J.A. Paramo, E. Quintanilla (1993). Malignant atrophic papulosis. A report of two cases with altered fibrinolysis and platelet function. Clin. Exp. Dermatol. 18, 441-444

5 Vicktor C., U. Schultz-Ehrenburg (2001). Papulosis maligna atrophicans (Köhlmeier-Degos). Hautarzt 52, 734-737

6 Farrell A. M., J. Moss, C. Costello, L.A. Fearfield, D. Woodrow, C.B. Bunker (1998). Br. J. Dermatol. 139, 708-712

7 Chave T.A., S. Varma, G.K. Patel, A.G. Knight (2001). Malignant atrophic papulosis (Degos’ disease): clinicopathological correlationsJEADV 15, 43-45

8 Sullivan G.W., H.T. Carper, W.J. Nowick, G.L. Mandell (1988). Inhibition of the inflammatory action of Interleukin-1 and Tumor Nekrosis Factor (alpha) on neutrophil function by Pentoxyfylline. Infect. Immun. 56, 1722-1729

9 Su W.P., A.L. Schroeter, D.A. Lee, T. Hsu, S.A. Muller (1985). Clinical and histologic findings in Degos syndrome (malignant atrophic papulosis). Cutis 35, 131-138

10 Atchabahian A., M.J. Laisne, F. Riche, C. Briard, J. Nemeth, P. Valleur (1996). Small bowel fistula in Degos’ disease: a case report and literature review. Am J Gastroenterol 91, 2208-2211

11 Black M.M., K. Nishioka, G.M. Levene (1973). The role of dermal blood vessels in the pathogenesis of malignant atrophic papulosis (Dego’s disease). Br J Dermatol 88, 213-219

12 Rocha H.E. (1985). Fibrinolysis in Dego’s disease. Thromb Haemostasis 54, 780

13 Daniel F., C. Foix, J.M. Gray et al. (1982). Papulose atrophiante maligne avec insuffisance de la fibrinolyse sanguine. Ann Dermatol Venerol 109, 763-764

14 Requena L., M.C. FarinaA. Barat (1998). Dego’s disease in a patient with acquired immunodeficiency syndrome. J Am Acad Dermatol 38, 852-856

15 Powell, Bordea, Wojnarowska, Farrell, Morris (1999). Benign familial Degos disease worsening during immunosuppression. Br J Dermatol 141, 524-527

16 Katz S.K., L.J. Mudd, H.H. Roenigk (1997). Malignant atrophic papulosis (Dego’s disease) involving three generations of a family. J Am Acad Dermatol 37

17 Kish L.S., D.P. Bruynzeel (1984). Six cases of malignant atrophic papulosis (Degos disease) occuring in one family. Br J Dermatol 111, 469-471

18 Thomson K.F., A.S. Highet (2000). Penile ulceration in fatal malignant atrophic papulosis (Degos disease). Br J Dermatol 143, 1320-1322

19 Metz J., A. Amschler, M. Henke (1980). Morbus Degos (Papulosis atrophicans maligna). Hautarzt 31, 108-110

20 Burg G, D. Vieluf, W. Stolz et al . (1989). Malignant atrophic papulosis. Hautarzt 40, 480-485

21 Olmos L., P. Laugier (1977). Ultrastructure de la maladie de Degos (rapport d’un noveau cas et revue de la litterature). Ann Dermatol Venereol 104, 280-293

22 Lee D.A., W.P.D. Su, T.J. Liesegang (1984). Ophthalmic changes of Degos’ disease (malignant atrophic papulosis). System Ophthalmol 91, 295-299

23 Stahl D., K. Thomsen, K. Hou-Jensen (1977). Dego’s disease treated with platelet-suppressive drugs. Lancet, July 2, 46-47 (letter to the editor)

24 Habbema L., L.S. Kish, T.M. Starink (1986). Familial malignant atrophic papulosis (Degos’ disease) – additional evidence for hereditary and benign course. Br J Dermatol 114, 134-135

25 Roenigk H.H., R.G. Farmer (1968). Degos’ disease (malignant atrophic papulisis): report of three cases with clues to etiologyJAMA 206, 1508-1514

26 Howsden S.M., S.J. Hodge, J.H. Herndon, R.G. Freeman (1976). Malignant atrophic papulosis of Degos: report of a patient who failed to respond to fibrinolytic therapy. Arch Dermatol 112, 1582-1588

27 Grilli R., M.-L. Soriano, M.-J. Izquierdo, M.-C. Farina, L. Martin, F. Manzarbeitia, L. Requena (1999). Panniculitis mimicking lupus erythematosus profundus. A new histopathologic finding in malignant atrophic papulosis (Degos’ disease). Am J Dermatopathol 21, 365-368

Degos disease (malignant atrophic papulosis) is a rare progressive, small and medium size arterial occluding disease, leading to tissue infarction initially involving the skin and later the gastrointestinal, ocular and central nervous systems.

The disease is characterized by papules that develop porcelain-white centres and telangiectatic borders. This is the clue to the underlying disease which can affect the gastrointestinal tract and central nervous system and may lead to death.

The skin biopsy places the pathologist at the centre of the diagnostic evaluation. (See biopsy plates below and under Images

Background

In 1941, in an article entitled “Multiple Hautrekrosen bei Thromboangiitis obliterans,” Kohlmeier described a case of a disease that has now been termed malignant atrophic papulosis (MAP) or Degos disease (DD). Degos recognized it as a distinct clinical entity in 1942.

Broadly speaking, DD is a vasculopathy or an endovasculitis. It is an occlusive arteriopathy involving small-calibre vessels. Specifically, it is a progressive, small- and medium-size arterial occluding disease, leading to tissue infarction and initially involving the skin. DD occurs both in a limited benign, cutaneous form and in a lethal multiorgan, systemic variant.

In the skin, DD initially manifests with erythematous, pink or red papules. These papules heal to leave scars with pathognomonic, central, porcelain white atrophic centers. These papules usually have a peripheral telangiectatic rim.

In the systemic variant of DD, the gastrointestinal tract is affected in 50% of cases. Intestinal perforation is the most severe complication and the most common cause of death in systemic DD. Other systems can also be involved; approximately 20% of cases of systemic DD involve the CNS. Systemic manifestations usually develop from weeks to years after the onset of skin lesions, or, in rare instances, they may precede the skin lesions.

Synonyms and related keywords

DD, malignant atrophic papulosis, papulosis atrophicans maligna, Kohlmeier-Degos-Delort-Tricot syndrome, Kohlmeier-Degos syndrome, Köhlmeier-Degos’ disease, Online Mendelian Inheritance in Man 602248, OMIM 602248, papuleuse maligne atrophiante, lethal cutaneous and gastrointestinal arteriolar thrombosis, fatal cutaneointestinal syndrome, thromboangiitis cutaneointestinalis disseminata, dermatite papulosquameuse atrophiante, MAP

Pathophysiology

The etiology and the pathophysiology of DD are unknown. Some have classified DD as a vasculitis, a mucinosis, or a thrombotic disorder. In most cases, no circulating immune complexes, antiendothelial cell antibodies, or anticardiolipin antibodies are isolated. Although, in some cases, antiphospholipid antibodies of uncertain significance are identified.

Some authorities suggest that DD involves a primary endothelial cell defect with secondary thrombosis, leading to infarctive changes. No evidence exists for antibodies to components of endothelial cells. Medications and toxic chemicals do not appear to induce DD.

The actual physical damage to blood vessels involves, at least in part, impaired fibrinolytic activity and alterations in platelet function. Classifying DD as a vasculitis may not be appropriate because inflammation of the vessel walls is minimal and because immune complexes have not been found in the vessel walls.

Three possible mechanisms for this pathology have been suggested: disturbance in immunity, viral infection, and abnormality in the clotting system of blood.

In familial cases, an autosomal dominant mode of inheritance has been suggested, but this is uncertain.

In molecular analysis of cases of DD with only cutaneous lesions , no paramyxovirus was identified by polymerase chain reaction (PCR).

Lab Studies

  • No specific laboratory test can be used to aid in diagnosing DD. In fact, most laboratory test results are normal, with the exception of the manifestation of anemia secondary to intestinal bleeding.
  • In 1 patient, laboratory examinations disclosed persistent elevations of the thrombin-antithrombin III (TAT) complex, plasmin-alpha 2 plasmin inhibitor complex (PIC), and cytotoxic T-cell subset (CD8 + CD11 – ), illustrating the coagulative, fibrinolytic, and immunologic implications of DD.
  • In a series of 3 patients with DD, prolonged euglobulin lysis time, increased plasminogen activator (PA) levels, and increased plasminogen activator inhibitor (PAI) activities were detected before and after a venous occlusion test, indicating an inhibition of fibrinolysis.
  • In a series of 3 patients with DD, electron microscopy demonstrated an increased number of Weibel-Palade bodies and a raised staining of von Willebrand factor in endothelial cells in 1 patient.
  • In a series of 3 patients, test results for coagulation and circulating anticoagulant were in the reference range.
  • In a series of 3 patients, the results of platelet adhesion showed decreased adhesion in 1 patient and increased adhesion in another patient. Platelet aggregation study results were in the reference range in 2 patients, and the results showed hyperactive spontaneous and induced aggregation in 1 patient.
  • Amounts of protein in the cerebrospinal fluid (CSF) and amounts of platelet aggregation have been reported as sharply increased in progressive stages of the disease. For example, laboratory results showed a gradual increase of CSF proteins (from 156 mg/dL to 602 mg/dL) and an extremely increased amount of platelet aggregation.
  • In DD, viruslike inclusions are frequently present in the endothelial cells and fibroblasts. C3 deposits and the presence of intracytoplasmic cylinders are also frequently present in the histiocytes.

Imaging Studies

  • MRI of the brain can show multiple cerebral infarctions accompanied by small hemorrhagic areas and gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) enhancement of the dura. They can also reveal intracerebral bleeding, subdural hemorrhage, and cord infarcts.
  • A cerebral angiogram may reveal narrowing and occlusion of small intracranial arteries. Specifically, a cerebral angiogram can depict stenosis, ectasia, and aneurysms involving the peripheral branch of arteries.
    EEG tests have shown generalized nonspecific slowing.
  • In some patients, electromyograms (EMGs) demonstrate axonal and demyelinating polyneuropathy.
  • With angiograms, stenoses can be observed in the celiac artery and the small arteries in the kidney.
  • In some patients, chest radiographs have depicted extensive calcification of the pericardium. Although pleural involvement and pericardial involvement have been reported in DD, constrictive pericarditis is most unusual, and radiographically demonstrable calcification of the pericardium has not been previously reported.

Other Tests

  • Endoscopy of the gastrointestinal tract (ie, stomach, esophagus, duodenum, colon, rectum) can show infarcted lesions or ulcers.
  • Laparoscopy of the intestine can show similar type lesions that manifest with white plaques with red borders on the serosal surface of the bowel and the peritoneum.

Histologic Findings

Early papules in DD are skin colored and can demonstrate a superficial and deep perivascular, periadnexal, and perineural chronic inflammatory cell infiltrate associated with interstitial mucin deposition. The overlying epidermis can show a mild vacuolar interface reaction, and, at this early stage, the histologic appearances can resemble tumid lupus erythematosus.

Fully developed papules can be raised with umbilicated porcelain white centers and a surrounding erythematous rim. Usually, wedge-shaped degeneration of collagen is present. A prominent interface reaction with squamatization of the dermoepidermal junction, melanin incontinence, epidermal atrophy, and a developing zone of papillary dermal sclerosis that resembles the early stages of lichen sclerosus et atrophicus in miniature can also be observed at histologic examination. These interface reactions are usually confined to the central portion of a punch biopsy specimen, corresponding to the central, porcelain white area seen clinically.

Histopathologic examination of the skin biopsy specimen can also show hyperkeratosis, epidermal atrophy, dermoepidermal separation, edema, and necrosis in the papillary dermis. Fibrinoid necrosis and thrombosis can be seen in the papillary dermis and in the vessels below the lesions. Others have noted that skin biopsy specimens show hyperkeratosis, atrophy of the epidermis, and necrobiosis of the collagen layer. Well-developed lesions with epidermal atrophy and hyperkeratosis overlying a wedge-shaped area of cutaneous ischemia extending into the deep dermis have also been observed. Superficial and deep perivascular lymphocytic infiltrate can be present at the edge of ischemic areas. Marked endothelial swelling and occasional platelet-fibrin thrombi can be present. The epidermis may show infarctive changes or scattered necrotic keratinocytes. Abundant acid mucopolysaccharides can be present in the dermis giving the appearance of a dermal mucinosis.

Direct immunofluorescence (DIF) yields conflicting findings with perivascular fibrin and complement in variable instances. An autopsy examination confirmed the clinical diagnosis of the syndrome by the finding of thromboangiitis of the Burger type, with bland infarcts of the small intestine and perforation of the jejunum. Microaneurysms of the bulbar conjunctival vessels have been described. Changes in the kidney manifest with thickening of the afferent glomerular arterioles and the capillary basement membrane.

Prognosis is poor when systemic involvement is found, but seems to be good in benign forms.

Gastrointestinal involvement may occur in up to 60% of cases – death may occur.

Patients with skin lesions only may have a good prognosis.

Approximately 15% of Degos’ disease exhibit long-term survival with disease often limited to the skin and with no history of catastrophic bowel or central nervous system involvement.

Mortality/Morbidity

Systemic DD is frequently fatal within 2-3 years from the onset of systemic involvement. The cause of death is usually intestinal perforation. However, the range of survival time from time of diagnosis varies from less than 1 year to more than 12 years. Other causes of death include bowel infarction, pleuropericardial pathology, and neurologic infarction and hemorrhage.

In 1 patient, in whom skin and abdominal symptoms occurred at the same time, death from bowel hemorrhage followed in 6 months.

In 1996, Subbiah et al described the neurologic features of a series of 15 patients with DD at the Mayo Clinic. All 15 patients had the typical skin lesions of DD, confirmed by skin biopsy. Long-term follow-up revealed death in 6 patients; 9 patients were nearly asymptomatic. Immunosuppressive and antiplatelet agents were of no benefit. CNS infarcts and hemorrhages with intravascular thrombi and without evidence of vasculitis were characteristic features at autopsy.

Prognosis Findings at 1st International Meeting on Degos Disease, March 18th-19th 2005

Patients with positive family history had no systemic involvement (ie no lethal outcome from Degos).

In the current study the mean age is 35.4 years.

A graph showed that 85-90% of patients who develop systemic involvement will do that within the first 6 years after the skin lesions appear. (However one patient is known who developed systemic involvement after 13 years). Statistics from our group of 20 patients show the same distribution of probabilities.

Almost 85% of those with systemic involvement developed their symptoms within the first three years after the appearance of the skin lesions.

There is no standard prognosis for patients with systemic involvement; each patient has to be examined separately.

It is possible to have GI involvement and not have any symptoms.

To discover this, patients would need to be monitored regularly, and many patients’ symptoms and data examined.