Chapter 7 Vasculitis 7

As already mentioned, the dermis normally contains are affected. The inflammatory cell infiltrate con- only a sparse amount of lymphocytes, mainly located sists mainly of neutrophils. The presence of nuclear around postcapillary venules. There are no neutrophils fragments from disintegrating neutrophils (leuko- or eosinophils (Bos et al. 1987). In response to inflam- cytoclasis) is a conspicuous phenomenon. matory stimuli, a variable number of one or several • II. Lymphocytic venular vasculitis: venules in the kinds of inflammatory cells migrate through the walls dermis and the dermal–subcutaneous interface are of venules and accumulate in the tissue. Even though affected. The perivascular cell infiltrates consist of these vessels take part in an inflammatory process, lymphocytes. we do not talk about vasculitis if there are no signs • III. Granulomatous venular vasculitis: venules in the of vascular damage. To call it vasculitis there should dermis and the dermal–subcutaneous interface are be, in addition to perivascular cell infiltrates, injury to affected and surrounded by small areas of necrotic the vessels visible under the light microscope and ex- tissue, in turn encircled by epithelioid cell granulo- pressed as thrombi and/or fibrinoid (i.e., eosinophilic mas and a sparse number of lymphocytes. and glossy) necrosis of the wall. The lesions (whether • IV. Neutrophilic arterial vasculitis: arterioles in the few or numerous) are always segmental (i.e., focal), deep dermis and arterioles and small arteries in the and engage only a very small part of the length of subcutis are affected. The inflammatory cell infil- the vessel. In the engaged segment the whole or only trate is strictly perivascular and mainly composed a part of the vessel‘s circumference may be involved. of neutrophils. Leukocytoclasis is prominent. Fibrin thrombi and wall necrosis are fresh lesions that • V. Lymphocytic/monocytic arterial vasculitis: arte- indicate an acute vascular injury or acute vasculitis. rioles in the deep dermis and arterioles and small There is also deposition in the tissue outside the ves- arteries in the subcutis are affected and surrounded sel of eosinophilic fibrinous (protein-rich) exudate by a well-demarcated mononuclear inflammatory and extravasation of erythrocytes. This is the result cell infiltrate. of necrosis of the vessel wall including the basement • VI. Granulomatous neutrophilic arterial vasculitis: membrane. However, extravasation of erythrocytes is small arteries in the subcutis and ascending arte- not per se a sign of acute vasculitis. It may occur with- rioles show neutrophilic leukocytoclastic vasculitis. out visible signs of damage to the wall, as is the case in In the surrounding tissue there are large necrotic scurvy, where the production of the collagen, support- areas surrounded by epithelioid cell granulomas ing the vessel wall is impaired, in senile, atrophic skin, and sometimes abscesses. and in the tissue around newly formed vessels, which • VII. Mixed group: venules in the dermis and at the are leaky (Fig. 22.5). dermal–subcutaneous interface are affected. In a While scrutinizing material comprising vascu- dense inflammatory cell infiltrate of mixed type lar skin lesions collected since the 1960s, the author there are dilated venules with protruding endothe- found that with respect to the histopathologic pattern, lial cells and/or conspicuously thick-walled venules, it is possible to discriminate six distinct categories of and in some cases simultaneously venules showing vasculitis, which the author has tried to anchor in the fibrinoid necrosis and/or thrombosis. literature. In a further category (category VII), a group of vasculitis is discussed, which includes entities and cases, which clinically are widely different, but histo- 7.1 pathologically show some similarities (Fig. 7.1): Category I: Neutrophilic Venular Vasculitis • I. Neutrophilic venular vasculitis: venules in the This kind of vasculitis is generally calledleukocytoclas- dermis and the dermal–subcutaneous interface tic vasculitis (synonyms are, among others: necrotiz- 36 7 Vasculitis

I. Neutrophilic venular II. Lymphocytic venular III. Granulomatous venular vasculitis vasculitis vasculitis

IV. Neutrophilic arterial V. Lymphocytic/monocytic VI. Granulomatous neutrophilic vasculitis arterial vasculitis arterial vasculitis

VII. Mixed group vasculitis Abnormalities in Arteriolosclerosis blood components

Arteriole-capillary Necrotic tissue Neutrophil Lymphocyte Venule Arteriolosclerosis Monocyte Plasma cell Thick-walled venule Nuclear dust Epithelioid cell Fig. 7.1 Diagram of vascular lesions 7.1 Category I: Neutrophilic Venular Vasculitis 37 ing vasculitis, hypersensitivity vasculitis, hypersen- typical phenomenon and often striking. Serious injury sitivity angiitis, allergic vasculitis, and anaphylactoid to vessels in the subepidermal region gives rise to ar- purpura). Spells of leukocytoclastic vasculitis may be eas of spongiosis and vesicles/bullae in the epidermis, triggered by bacterial and viral infections and drugs. and sometimes to ulceration. When the acute phase Sometimes an eruption appears shortly after an inci- declines the histopathologic pattern becomes nonspe- dent of sore throat due to streptococcal infection or cific and neutrophils are replaced by macrophages and after a spell of gastrointestinal malaise. It may appear lymphocytes. without any other symptoms, but can be accompanied by fever and increased erythrocyte sedimentation rate (ESR), or hematuria indicating renal involvement. 7.1.3 Also leukocytoclastic vasculitis may be an expres- Pathogenesis sion of systemic diseases such as classic systemic poly- Investigations have shown that leukocytoclastic vas- arteritis nodosa, systemic lupus erythematosus and culitis, which is not caused by direct invasion of bac- rheumatoid arthritis (Weedon 1997). teria or virus, is an expression of the hypersensitivity reaction type III. In the blood, soluble antigens from bacteria, virus or drugs bind to antibodies and form 7.1.1 antigen–antibody complexes (immune complexes). Clinical Appearance The size of the immune complexes, which is critical, The patient exhibits one or several spells of a polymor- depends on the concentration of the two components phic, widespread, or localized rash. This includes dif- antigen and antibody. A high excess of antibody gives ferent-sized reddish papules (sometimes coalescing to rise to large complexes. These are rapidly trapped and plaques), petechiae and ecchymoses. Some papules are phagocytosed by macrophages lining the sinusoids of markedly edematous and have a central vesicle/bulla the liver, spleen and bone marrow, and consequently or are ulcerated/crusted. If the outbreak is localized, are put out of action. A high excess of antigen gives the most common areas affected are the lower legs. rise to small and harmless complexes. However, a The rash is called “palpable purpura”, a term often used moderately high excess of antibody forms medium- by dermatologists as synonymous with leukocytoclas- sized complexes which are small enough to circulate tic vasculitis. However, sometimes purpura is the only for a long time but large enough to be caught in small manifestation of leukocytoclastic vasculitis. In pa- vessels and cause damage. Antibody in the immune tients with palpable lesions, petechiae are common in complexes is mainly IgG and IgM. areas exposed to pressure and may be found under the It has been shown by means of electron microscopy elastic bands of underwear, or arise in normal-appear- and immunofluorescence that these complexes are ing skin after a blood pressure check. The rash usually taken up focally by the endothelial cells and are stored vanishes spontaneously in a few weeks with hyperpig- in the wall of the venules and in the perivascular tissue mentation or atrophic scars, or without any residue. before any damage appears in the vessel. The inflam- Ulcerations on the lower legs may remain and enlarge, matory process leading to tissue destruction is trig- and thus imitate varicose ulcers. gered when complement binds to IgG or IgM antibod- ies in the complexes and becomes activated. The three activated components of complement C3a, C4a and 7.1.2 C5a (also called anaphylatoxins) cause direct injury to Histopathologic Appearance tissue cells. Like histamine and serotonin they induce Different-sized venules at all levels of the dermis are venular leakage, and attract neutrophils (Sect. 5.2.1). affected, but the most conspicuous changes are of- Neutrophils phagocytose the immune complexes. ten seen in the upper half. If the only clinical sign is When the neutrophils die and disintegrate they release purpura, the vasculitis is discreet and confined to the hydrolytic enzymes which contribute to the tissue subepidermal area. The pattern is variegated. There damage. The consumption of complement gives rise are fibrinoid necrosis of vessel walls with or without to hypocomplementemia (Braverman and Yen 1975; thrombosis, and a fibrinous exudate and red blood cells Lawley and Kubota 1990). in the perivascular tissue. In fresh lesions the inflam- matory cell infiltrates consist mainly of neutrophils, but there also are some lymphocytes, and sometimes a substantial number of eosinophils. The presence of nuclear dust due to disintegration of neutrophils is a 38 7 Vasculitis

Fig. 7.2 Neutrophilic venular vasculitis. a Lower leg with rest of them are more or less obscured by nuclear fragments and densely set different-sized papules and plaques. The plaques are fibrinous exudate. The tissue is edematous and in the left upper covered with crusts, some of which are encircled by tiny scales. corner there is a subepidermal vesicle in the making. Note also b Only one unaffected venule is clearly discernible (arrow). The the many keratinocytes with intracellular edema. H&E, ×200

7.1.4 Case 3. Neutrophilic Venular Vasculitis Examples This 66-year-old woman had had tonsillitis 8 years previously followed by glomerulonephritis that healed. Case 1. Neutrophilic Venular Vasculitis Thereafter vasculitis-like or bullous lesions now and A 36-year-old woman presented with a striking then appeared on the ankles. Also some lesions ulcer- eruption of erythematous and edematous papules ated. and plaques, mainly located on the lower legs. Some Investigation of a clinically non-bullous lesion re- plaques showed a regressing bulla, others were crusted; vealed marked leukocytoclastic vasculitis affecting ve- also most papules had a small vesicle, a superficial ul- nules in the dermis and upper subcutis. Neutrophils ceration or a crust on the top (Fig. 7.2a). The eruption and nuclear fragments dominated the cell infiltrates, appeared suddenly 2 weeks after an infection of the but there were also a fair number of eosinophils and upper respiratory tract. Histopathologic investigation histiocytes. The epidermis contained rather large, ve- revealed typical leukocytoclastic vasculitis. siculopustules filled with exudate, neutrophils and erythrocytes (Fig. 7.3). Case 2. Neutrophilic Venular Vasculitis A 77-year-old man suffered from colicky abdominal pain for 2 months. Shortly after the beginning of this 7.1.5 distress he experienced two spells of hemorrhagic, ve- Variants of Leukocytoclastic Vasculitis sicular efflorescences on the lower legs. The ESR in- This group includes Henoch-Schönlein purpura, in- creased to 68 mm/h. The urine contained albumin and fantile acute hemorrhagic edema of the skin, urticarial many red blood cells. vasculitis, and recurrent cutaneous necrotizing eosin- Histologic investigation revealed typical leukocyto- ophilic vasculitis. clastic vasculitis with marked wall necrosis, extrava- sation of red blood cells, dense infiltrates of neutro- phils, and a conspicuous number of nuclear fragments 7.1.5.1 (Fig. 7.2b). Henoch-Schönlein Purpura Henoch-Schönlein purpura has a predilection for chil- dren aged 2 to 4 years, but can also affect older chil- dren and adults. The rash is most prominent on the 7.1 Category I: Neutrophilic Venular Vasculitis 39

Fig. 7.3 Neutrophilic venular vasculitis. a Totally necrotic ven- ule. The wall is massively permeated and surrounded by nuclear fragments and erythrocytes. b Another thrombotic and necrotic venule is surrounded by nuclear fragments, a few leukocytes, and a fair number of histiocytes (macrophages), one of which is indicated (arrow). c There is a mainly intraepidermal vesicle containing neutrophils and a conglomerate of erythrocytes (ar- row). At the base the vesicle is connected with a papilla com- prising a necrotic vessel (small arrow), fibrinous exudate, and erythrocytes. H&E, ×400

lower legs and buttocks and is accompanied by arthri- tis and/or gastrointestinal symptoms, and sometimes nephritis. Histologic investigation shows leukocyto- clastic vasculitis. Antibodies in the complexes are IgA, which are activated by the alternative pathway (Sect. 4.3.1) (Lawley and Kubota 1990; Reinauer et al. 1995).

7.1.5.2 Infantile Acute Hemorrhagic Edema of the Skin Infantile acute hemorrhagic edema of the skin is seen in children less than 2 years old. The children have one or several spells of hemorrhagic efflorescences to- gether with edema, mainly localized to the limbs and face. Often there is a history of a recent infection and/ or medication. There could be slight fever, but visceral involvement is uncommon. The rash spontaneously vanishes within 1 to 3 weeks. Histologic investiga- tion displays leukocytoclastic vasculitis (Legrain et al. 1991).

7.1.5.3 Urticarial Vasculitis Painful, non-pruritic, urticaria-like wheals that re- main longer than ordinary urticaria efflorescences and histologically show leukocytoclastic vasculitis are called urticarial vasculitis. Some lesions are purpu- ric. Reported associated symptoms are angioedema, arthralgia, and abdominal pain. Infrequently these patients may suffer from a connective tissue disease. Probably urticarial vasculitis is only a milder variant of leukocytoclastic vasculitis. However, the definition of urticarial vasculitis is not always as clear-cut, and some authors do not include fibrinoid necrosis and leukocytoclasis as a requirement (Lawley and Kubota 1990; Mehregan et al. 1992). 40 7 Vasculitis

7.1.5.4 However, lymphocytic venular vasculitis certainly Recurrent Cutaneous Necrotizing Eosinophilic exists. The most common cause is drugs (Soter et al. Vasculitis 1976; Massa and Su 1984). Investigations have re- In many cases of leukocytoclastic vasculitis there is a vealed that lymphocytic vasculitis is associated with more or less massive admixture of eosinophils. There normocomplementemia, while leukocytoclastic vas- is probably no reason to discriminate these cases from culitis often shows hypocomplementemia (Soter et al. other cases of leukocytoclastic vasculitis. However, 1976; Massa and Su 1984). Soter et al. even observed Chen et al. (1994) described three patients with re- stimulated lymphocytes in several of their patients. current episodes of pruritic, erythematous, purpuric papules, and angioedema associated with peripheral blood eosinophilia. Histologic investigation revealed 7.2.1 leukocytoclastic vasculitis with cell infiltrates consist- Clinical Appearance ing exclusively of eosinophils. In one of the patients it The skin eruptions are episodic and variable and may was possible to prove the presence of adhesion mol- show papules, nodules and plaques, which are some- ecules for eosinophils in involved vessels. times vesicular and/or purpuric. The clinical appear- ance can be indistinguishable from that of leukocyto- clastic vasculitis (Soter et al. 1976; Massa and Su 1984; 7.1.5.5 Smoller et al. 1990). Pustular Vasculitis of the Hands Strutton et al. (1995) described six patients, all women, with painful sterile nodules and plaques on the hands 7.2.2 and fingers accompanied by fever and neutrophilic leu- Histopathologic Appearance kocytosis. The cause was unknown. Biopsy specimens As in category I, venules in the dermis and superficial showed neutrophilic venular vasculitis with massive, subcutaneous tissue are affected and show thrombosis abscess-like perivascular infiltrates of neutrophils and and/or fibrinoid wall necrosis, but the perivascular cell nuclear fragments around the vessels. The eruptions infiltrates are composed of lymphocytes, sometimes responded to prednisone, but not to antibiotics. with an admixture of eosinophils. There are no neu- trophils.

7.1.6 Differential Diagnosis 7.2.3 • Pyogenic bacteria or virus, locally invading the Pathogenesis tissue, may cause leukocytoclastic vasculitis (Sect. The underlying mechanism in lymphocytic venular 20.1.5; Fig. 20.2d). vasculitis is not as well understood as that in leukocy- • Langerhans cell histiocytosis may contain scattered toclastic vasculitis. Some kind of cell-mediated hyper- venules with neutrophilic vasculitis (Sect. 21.4; sensitivity reaction has been suggested (Carlson et al. Figs. 21.3c and 21.4b). 1996). The possibility that the lymphocytic vasculitis • Vascular lesions due to abnormalities in blood com- may represent a declining leukocytoclastic vasculitis ponents (Chapter 8). has also been suggested (Smoller et al. 1990). How- • Arteriolosclerosis (Chapter 9). ever, in lymphocytic vasculitis there are venules with fresh thrombi and wall necrosis surrounded by infil- trates composed only of lymphocytes. In resolving le- 7.2 sions of leukocytoclastic vasculitis there is a mixed cell Category II: Lymphocytic Venular Vasculitis infiltrate consisting of macrophages, lymphocytes and The existence of a lymphocytic venular vasculitis as neutrophils, while foci of acute vasculitis are lacking. a specific clinicopathologic entity comparable to leu- kocytoclastic vasculitis was described by Soter et al. (1976), but was later the subject of much debate and 7.2.4 was called into question (Massa and Su 1984; Jones Examples 1985; Smoller et al. 1990; Carlson et al. 1996). In part this was due to disagreement on the histopathologic Case 4. Lymphocytic Venular Vasculitis requirements for lymphocytic vasculitis, and in part A 39-year-old woman had over several years now to complicated and confusing classification proposals and then experienced single erythematous swellings (Carlson et al. 1996). on different sites of the body. She presented with a 7.3 Category III: Granulomatous Venular Vasculitis 41

Fig. 7.4 Lymphocytic venular vasculitis. a Two venules in the ×250. b Close-up of the larger vessel shows fibrinoid wall ne- middle of the dermis are surrounded by a dense infiltrate of crosis. The lumen is occluded by a thrombus of erythrocytes, lymphocytes. The small structure to the right is a nerve (arrow); mononuclear cells and nuclear fragments. H&E, ×400

circumscribed erythematous and edematous lesion, nucleus, distinct chromatin and a nucleolus. Scattered about 50 mm in diameter, on the dorsal aspect of the vessels contained a fibrin thrombus and showed wall left thigh. The lesion was very painful to the touch. A necrosis. Extravasation of erythrocytes was conspicu- drug reaction was suspected, but the cause of the le- ous. Inflammatory cells had invaded the epidermis, sion was never determined. which was spongiotic and edematous (Fig. 7.5). The biopsy specimen comprised dermis and a sub- stantial part of subcutaneous tissue. At all levels of the dermis and at the dermal–subcutaneous interface 7.2.5 there were medium-sized or small, well-defined, dense Differential Diagnosis infiltrates of lymphocytes. In the center of several of • Vascular lesions due to abnormalities in blood com- these infiltrates there was a necrotic venule occluded ponents (Chapter 8). by a thrombus. The wall of the vessel was necrotic and • Pityriasis lichenoides et varioliformis (Sect. 26.3.2). there were many extravasated erythrocytes. The epi- • Direct invasion of the vessel by bacteria, which is dermis was normal (Fig. 7.4). probably the case in the lesions demonstrated in Figs. 12.2c and 18.4e. Case 5. Lymphocytic Venular Vasculitis A 41-year-old man was receiving treatment with the β-receptor blocking drug atenolol for hypertension 7.3 when he suddenly developed an itchy, erythematous, Category III: Granulomatous Venular vesicular, and purpuric eruption on the hands and Vasculitis feet. Atenolol, suspected to be the cause, was with- Case 6 discussed below is one of only two cases the drawn and the exanthema subsided. As a test he was author has observed; unfortunately the other one was then given one tablet of the drug and reacted with fe- not documented. The course, and the clinical and his- ver and a new eruption. topathologic patterns are notable, but difficult to iden- A biopsy specimen was taken from the thenar re- tify in the literature. Winkelmann (1980) described a gion. In the papillae and upper dermis within a rather rare non-infectious necrotizing granulomatous dis- well-demarcated area there were dense, mainly peri- ease in the dermis that, according to him, had no other vascular cell infiltrates. These were composed of or- name or description and only rarely was investigated. dinary small lymphocytes and larger slightly atypical He did not describe the clinical appearance, but the lymphocytes (stimulated lymphocytes) with a light photomicrographs show necrotic venules surrounded 42 7 Vasculitis

Fig. 7.5 Lymphocytic venular vasculitis. a In the upper dermis, tains scattered irregular and different-sized lymphocytes and a partly between two edematous rete pegs (asterisks), there is a mitotic figure in anaphase (small arrows). b Another infiltrate dense cell infiltrate surrounding a necrotic thrombotic venule contains a partly necrotic vessel filled with disintegrating eryth- (large arrow). The cell infiltrate is slightly atypical and con- rocytes. H&E, ×600

by epithelioid cell granulomas and a slight admixture was negative and the complement value was normal. of lymphocytes in the dermis, a pattern very like that Biopsy specimens were taken from the wrist and fore- observed in Case 6. arm. The triggering cause in Case 6 was never identified. Both specimens included the whole dermis and The epithelioid cell granulomas indicate a cell-medi- showed the same pattern. At all levels of the dermis ated immunologic reaction. there were several scattered small epithelioid cell granulomas, which embraced a necrotic venule and a hemorrhagic necrosis. There was a slight admixture of 7.3.1 lymphocytes. The epidermis was normal (Fig. 7.6). Example

Case 6. Granulomatous Venular Vasculitis 7.4 A 56-year-old alcoholic man, who for a long time had Category IV: Neutrophilic Arterial Vasculitis been treated with the β-receptor blocker alprenolol This pattern of vasculitis was first described more and the diuretic amiloride, presented with an itch- distinctly by Diaz-Perez and Winkelmann (1974) as ing eruption that had developed during the previous benign cutaneous polyarteritis nodosa. Their series 4 days. On the dorsal aspect of the hands, forearms included 23 patients with a prolonged and benign and the nape of the neck there were closely set small, disease course. Later Daoud et al. (1997) analyzed 79 slightly scaling, brownish-red papules and petechiae. cases with the diagnosis of cutaneous periarteritis no- On the dorsal aspect of the right hand the papules co- dosa seen at the Mayo Clinic between 1973 and 1995, alesced and nearly covered the area. The palms were which did not include the series of Diaz-Peres and not affected. The eruption disappeared completely af- Winkelmann. They generally verified the findings of ter a short time, and did not return. Only topical treat- Diaz-Peres and Winkelmann. The disease course was ment was given. prolonged, but systemic periarteritis nodosa did not With the exception of a markedly elevated serum occur. In these two series, at least four patients were γ-glutamyl-transpeptidase, indicating impaired liver children. A further four children suffering from cuta- function (probably due to over-consumption of alco- neous periarteritis nodosa with a benign course have hol) all routine laboratory values were normal. Cryo- been described by Sheth et al. (1994). globulins were not found. Direct immunofluorescence 7.4 Category IV: Neutrophilic Arterial Vasculitis 43

7.4.3 Pathogenesis In many cases it is not possible to determine the trig- gering cause of this kind of vasculitis. However, pre- vious or concurrent acute infections, especially with streptococci, have been noted (Daoud et al. 1997; Sheth et al. 1994). The disease has also been linked to hepatitis B and C virus infections, but this could not be verified in the series of Daoud et al. Notably, in the series of Daoud et al., five patients had inflammatory bowel disease (four had Crohn disease, and one had ulcerative colitis). Provided the lesions in these pa- tients really did meet the histopathologic inclusion criteria of neutrophilic arterial vasculitis, inflamma- tory bowel diseases may give rise to different kinds of nodular vasculitis (Sect. 7.6).

Fig. 7.6 Granulomatous venular vasculitis. Lesion in the upper half of the dermis. There is an elongated hemorrhagic necrosis, 7.4.4 at the top of which is a necrotic venule (large arrow). The ne- Examples crotic area includes two smaller vessels (small arrows) and is en- circled by a wide brim of epithelioid cells and a sparse number Case 7. Neutrophilic Arterial Vasculitis of lymphocytes. H&E, ×250 A 35-year-old-man had an infiltrated area on the leg. The ESR was 104 mm/h. A biopsy specimen was taken; the question at issue was collagenosis. 7.4.1 Histologic investigation revealed a single affected Clinical Appearance small artery located in the subcutaneous tissue. A Most patients have spells of painful and slowly re- fresh thrombus with fibrinoid wall necrosis and break- gressing nodules. The location could be anywhere, but through into the surrounding tissue was observed. the lower extremities are the most common sites. In The perivascular tissue was edematous and permeated the series of Diaz-Perez and Winkelmann, livedo re- with neutrophils and a fair number of eosinophils. The ticularis (see Glossary) was observed in 78% of the pa- lesion was circumscribed; no other changes of impor- tients and ulcerations were noted during the course in tance were seen in the specimen (Fig. 7.7). 39%. Corresponding figures in the series of Daoud et al. were 56% and 50%. The only consistent laboratory Case 8. Neutrophilic Arterial Vasculitis finding described was an elevated ESR (Diaz-Perez A 5-year-old boy from the age of 18 months had had and Winkelmann 1974; Daoud et al. 1997). spells of fever and painful nodules on the arms and legs including the soles. A biopsy specimen showed a single affected small 7.4.2 artery in the subcutis. The vessel was partly thrombotic Histopathologic Appearance and surrounded by a circumscribed large and dense Histopathologic investigation shows vasculitis in arte- perivascular infiltrate of neutrophils with a slight ad- rioles in the lower dermis and/or small arteries in the mixture of eosinophils. There was a small rupture in superficial subcutaneous tissue. Usually only a single the wall (Fig. 7.8). affected vessel is seen in a punch biopsy specimen (Sect. 2.2; Figs. 2.1 and 2.2). The specimen shows fibri- noid wall necrosis with infiltrates of neutrophils and 7.4.5 nuclear fragments with an admixture of eosinophils. Differential Diagnosis The inflammatory reaction is confined to the area • Classic systemic polyarteritis nodosa. The histo- around the vessel (Diaz-Perez and Winkelmann 1974; pathologic pattern in affected vessels is the same as Daoud et al. 1997). in so-called benign periarteritis nodosa, but larger vessels than those in the skin and upper subcutis (i.e., medium-sized arteries of different organs such 44 7 Vasculitis

Fig. 7.7 Neutrophilic arterial vasculitis. a A single small artery the arrow the vessel wall is very thin and close to disruption. in the subcutaneous tissue contains a fresh thrombus and is sur- b At this level the breakthrough of the wall is evident (arrows). rounded by a well-circumscribed neutrophilic cell infiltrate. At H&E

as heart, liver, kidney and gastrointestinal tract) are 7.5.2 affected. Hypertension, fever and weight loss are Histopathologic Appearance common symptoms in the systemic disease, but are One or two vessels (Sect. 2.2; Figs. 2.1 and 2.2) show not seen in so-called benign periarteritis nodosa. thrombosis and wall necrosis and are surrounded by a However, sometimes leukocytoclastic venular vas- well-demarcated infiltrate of mononuclear cells com- culitis in the dermis is a symptom in systemic poly- posed of lymphocytes or monocytes, or by a mixture arteritis nodosa. of both. • Microscopic polyarteritis (polyangiitis) nodosa refers to a variant of systemic polyarteritis, which engages small arterial vessels, primarily in the kid- 7.5.3 neys, and gives rise to rapidly progressing glomeru- Examples lonephritis (Lhote et al. 1996). Case 9. Lymphocytic Arterial Vasculitis A 35-year-old man for about 2 years had experienced 7.5 spells of skin lesions with scattered small ulcerations Category V: Lymphocytic/Monocytic on the lower legs and feet associated with nocturnal Arterial Vasculitis pains in the feet and ankles. The initial investigation revealed marked livedo reticularis on the lower legs and feet and on the medial side of the lower legs also 7.5.1 purpura and slight infiltration (Fig. 7a). During the Clinical Appearance subsequent observation, about 2 years later, he had The lesions are located on the lower legs and appear had two more spells and presented with scattered in- as spells of painful erythematous infiltrates or nodules filtrations up to 10 mm in diameter, minute superficial with or without livedo reticularis. However, in some ulcerations and shallow scars. Laboratory investiga- cases the only symptom is livedo reticularis. The dis- tions showed no evidences of autoimmune disease and ease is chronic and benign, but during the course some all routine blood tests including electrophoresis were lesions may ulcerate. Thus the clinical pattern is very normal. similar to that described in Category IV. A biopsy specimen was taken from the knee region 7.5 Category V: Lymphocytic/Monocytic Arterial Vasculitis 45

Fig. 7.8 Neutrophilic arterial vasculitis. a A single small artery shows a small rupture in the wall (arrow). The cell infiltrate con- (arrow) in the subcutaneous tissue is affected and surrounded sists of neutrophils. H&E by a well-circumscribed inflammatory cell infiltrate. b Close-up

at the first visit. The changes were confined to a single dermis was otherwise normal. The epidermis was also arteriole located close to a group of sweat glands at the normal (Fig. 7.10). dermal–subcutaneous border. The vessel was occluded by a thrombus of disintegrating red blood cells and fi- Case 11. Presumably Monocytic Arterial Vasculitis brin. A part of the wall was edematous and penetrated The patient, a 41-year-old previously healthy woman, by erythrocytes and some inflammatory cells. The sur- had for 7 months experienced a painful infiltrate on rounding small, dense, well-demarcated infiltrate con- the medial aspect of the left lower leg, and for a month sisted of lymphocytes with a slight admixture of cells a smaller one above the medial right malleolus. The with a rounded nucleus and a small distinct nucleolus. overlying skin was erythematous, but there was no ul- There were no eosinophils or neutrophils (Fig. 7.9). ceration. A biopsy specimen was taken from the infiltrated Case 10. Monocytic/Lymphocytic Arterial Vasculitis area on the left leg and 2 weeks later another specimen A 38-year-old woman had since about two years no- from the lesion on the right leg. The material was cut ticed a livedo reticularis pattern on the lower legs into several sections at different levels and included without nodules or ulcerations. The results of the labo- dermis and superficial subcutaneous tissue. Investiga- ratory investigations and follow up are lacking. tion disclosed scattered and similarly affected arterioles A biopsy specimen was taken from the cyanotic net at the dermal–subcutaneous interface. In one of the on the frontal aspect of the lower leg. It comprised der- specimens two engaged arterioles were observed. In mis, but no subcutaneous tissue. In the deep dermis at one of these there was total wall necrosis with perfora- the lower limit of the specimen a single affected arte- tion into the surrounding tissue. A well-demarcated riole was observed. It could be followed only in a few broad band of large and closely packed mononuclear sections. The wall of the vessel was necrotic and sur- cells surrounded the necrotic wall and was in turn rounded by a well-circumscribed ring of inflammatory encircled by a ring of loose connective tissue and cells. Close to the vessel, the cell infiltrate consisted of lymphocytes. The mononuclear cells had a large, oval mononuclear cells larger than ordinary lymphocytes, or round, and somewhat irregular nucleus, some of and at the periphery mainly of small lymphocytes. which contained a distinct nucleolus. In a single sec- There were no eosinophils or neutrophils. The lumen tion two giant cells with a few clustered nuclei were of the vessel was filled with disintegrating cells. The observed. In another section there was a single mitotic 46 7 Vasculitis

Fig. 7.9 Lymphocytic arterial vasculitis. a Livedo reticularis. At the arrow, smooth muscle cells of the wall are discernible. To b The arrow indicates the affected vessel, an arteriole, located the right there is a small peripheral nerve (arrowhead) situated close to a sweat gland group at the dermal–subcutaneous in- between the vessel and the sweat gland group seen in b. H&E, terface; ×125. c Close-up shows the thrombotic vessel which is ×250 surrounded by a circumscribed infiltrate of small lymphocytes.

Fig. 7.10 Monocytic/lymphocytic vasculitis. Arteriole in the deep dermis. The wall of the vessel is necrotic and the lumen is filled with disintegrating cells. A dense and well-circumscribed band of mononuclear cells, larger than ordinary lymphocytes, surrounds the vessel. H&E, ×400 7.5 Category V: Lymphocytic/Monocytic Arterial Vasculitis 47

Fig. 7.11 Monocytic arterial vasculitis. a In the center of the le- sion there is an arteriole with wall necrosis and rupture into the surrounding tissue (arrow). Inflammatory cells and a peripheral ring of loose connective tissue encircle the lesion; ×200. b An- other section of the same arteriole shows a totally necrotic vessel embedded in a dense infiltrate of large mononuclear cells and numerous nuclear fragments, but no neutrophils; ×400. c This section contains in addition to mononuclear cells, two multi- nucleated giant cells (arrows); ×400. H&E

figure. Nuclear fragments were conspicuous around Wegener granulomatosis was suspected, but could not the necrotic vessel wall. At another level detached be verified (biopsy specimen from the nasal mucosa endothelial cells and nuclear fragments occluded the was negative). No other autoantibodies were detected; lumen. Eosinophils and neutrophils were not seen in thus systemic disease could not be proved. There was the core of the lesion. In the immediate surroundings no evidence of hepatitis A, B or C virus infection, or there were dilated venules and scattered inflammatory of borreliosis. No circulating antigen–antibody com- cells of different types. The epidermis was essentially plexes or cryoglobulins were found; complement anal- normal (s. Figs 2.2 and Fig. 7.11). ysis was normal and no deposition of IgM, IgG, IgA, Two months later the lesion on the left lower leg or C3 was found in the tissue. had ulcerated and the patient was referred to the der- At the time of writing the patient was still regularly matology department at the university hospital. On monitored at the hospital. The first ulceration healed, admission there was a 30×15 mm large, fibrin-cov- but over the years new lesions developed, some of ered ulceration with irregular borders on the medial which ulcerated. She has mainly been treated with oral aspect of the left lower leg. On the right medial mal- corticosteroids. At a check-up about 8 years after her leolus an erythematous patch, 20 mm in diameter, was first consultation she had been free from ulcerations noted. Laboratory investigation revealed moderately for a year by means of a small maintenance dose. She elevated ESR, markedly increased serum IgA, and was in good condition, had no symptoms, and was at antineutrophilic cytoplasmic antibodies (c-ANCA). work. 48 7 Vasculitis

Case 12. Arterial Vasculitis in Organization there was no evidence for autoimmune diseases or A 64-year-old woodwork teacher was hospitalized for heart disease. Virus serology was negative. There were investigation. For about a year he had had erythema- no cryoglobulins, and the platelet aggregation test was tous nodules on the lower legs. He was otherwise negative. He was given sulfasalazine and a diuretic, healthy and did not use drugs. On both lower legs and healed. there were scattered erythematous or bluish red infil- A biopsy specimen was taken from an infiltrated trates up to 20 mm in diameter without ulcerations. area and included a fair part of the subcutis. Close to There was also a slight edema, but no livedo reticularis the deep margin there was a small artery occluded by pattern. Laboratory investigation was normal. Thus, a thrombus in organization. In some sections there

Fig. 7.12 Arterial vasculitis in organization. a A small artery in cells; ×200. c Close-up of another section displays the smooth the subcutis is occluded by a thrombus in organization and sur- muscle cells of the vessel wall; ×400. d Markedly dilated thin- rounded by granulation tissue; ×100. b Close-up shows a gap walled vessels in the upper half of the dermis indicate stasis. In in the vessel wall (arrowheads). Both the gap and the lumen the right lower corner there is a group of proliferating capillar- are filled with granulation tissue. The area around the vessel ies; ×100. H&E is richly vascularized and densely infiltrated by inflammatory 7.6 Category VI: Granulomatous Neutrophilic Arterial Vasculitis 49 was a gap in the vessel wall plugged with fibrous tissue, nism? Presumably the large cells observed in Case 10 testimony to a previous rupture. There was a wide area and Case 11 are monocytes which when stimulated of richly vascularized granulation tissue (Sect. 5.2.4) become macrophages with the ability to form giant permeated with inflammatory cells of different kinds cells and, if not further stimulated, give rise to giant including many eosinophils and neutrophils; however, cells with only a few nuclei (Dugast et al. 1997) (Sect. close to the vessel most cells were lymphocytes. Also, 5.3.3.1). Investigations at the molecular level (at that there were a conspicuous extravasation of erythro- time not possible to perform) could have been of great cytes and a massive deposition of hemosiderin. No value. epithelioid cell granulomas or abscesses were noted. Case 12 demonstrates arterial vasculitis in healing. The middle and upper parts of the dermis contained In this stage it is not possible to distinguish with cer- several markedly dilated thin-walled vessels, indicating tainty between a neutrophilic and a mononuclear arte- stasis. The epidermis was flat, but otherwise normal rial vasculitis. (Fig. 7.12). In most cases of livedo reticularis and livedo reticu- laris with vasculitis the triggering cause cannot be de- termined. It is known that some drugs may give rise to 7.5.4 livedo reticularis, the most common of which is aman- Comment tidine used for Parkinson disease (Litt 2001). As in category IV, arterial vessels are affected and the lesions are circumscribed, but the inflammatory cell infiltrate is composed of mononuclear cells. Lympho- 7.6 cytic/monocytic arterial vasculitis is difficult to anchor Category VI: Granulomatous Neutrophilic in the literature because of incomplete and confusing Arterial Vasculitis histopathologic description and confusing nomen- clature. Feldaker et al. (1955) compared two clinical groups called “livedo reticularis with summer ulcer- 7.6.1 ations” and “livedo reticularis with ulcerations during Clinical Appearance the fall and winter”. They found that the patterns were As in categories IV and V, the patients suffer spells of generally the same in the two groups, but in some pa- painful, erythematous infiltrates or bluish-red nodules tients arteries and in some veins were affected. Bard on the lower legs, which may ulcerate. and Winkelmann (1967) discussed the histopathologic pattern in lesions they called livedo vasculitis, though none of the nine patients displayed livedo reticularis. 7.6.2 The involved vessels were described as arterioles and Histopathologic Appearance were located at the sweat gland level. The perivascu- Usually only one affected artery is observed and shows lar cell infiltrate was circumscribed and composed of thrombosis and wall necrosis with dense infiltrates of lymphocytes, a pattern in accordance with that found neutrophils and nuclear fragments in and around the in Case 9. vessel wall, which may develop into an abscess. There The histopathologic pattern displayed in Case 9, a are also widespread areas of necrosis both in the sub- thrombosed arteriole surrounded by a discreet infil- cutaneous tissue and in the dermis. Necrotic areas are trate of small lymphocytes, is in the author’s experience surrounded by a brim of histiocytes and epithelioid rather common and mostly accompanied by livedo cells with an admixture of giant cells of Langhans or reticularis. For the author it symbolizes a distinct and foreign-body type. Even small epithelioid cell granu- seemingly rather benign vasculitis, and is called here lomas without necrosis may be seen in the upper der- livedo reticularis vasculitis. However, livedo reticu- mis. laris is not always present and may even be a symptom Necrotic areas sometimes include one or several in category IV vasculitis and in arteriolosclerosis. Fur- necrotic venules. These are an integral part of the ne- thermore, Case 11 with the protracted course and the crotic tissue and thus secondary to the arterial throm- histopathologic pattern with large mononuclear cells bosis, and not the cause of the lesion. Also abscesses, and giant cells with a few nuclei, provokes thought. if present, may be surrounded by richly vascularized Are the patterns demonstrated in cases 9–11 expres- granulation tissue. Altogether the pattern may be sions of different kinds of mononuclear vasculitis with highly variegated and confusing if the biopsy speci- different genesis or do they represent different ages or men contains only a part of the lesion. grades of severity of lesion caused by the same mecha- 50 7 Vasculitis

7.6.3 A biopsy specimen taken from the lower leg in- Examples cluded dermis and the dermal–subcutaneous interface. The epidermis was normal. In several sections a single, Case 13. Granulomatous Neutrophilic Arterial severely affected ascending arteriole could be followed Vasculitis from the dermal–subcutaneous interface to the mid- This 60-year-old man suffered from Crohn disease. dermis. Epithelioid cells, scattered multinucleated gi- For 5–6 years he had experienced erythematous le- ant cells and lymphocytes surrounded the vessel. The sions with petechiae and a small central ulceration infiltrate was mixed up with mononuclear cells some- on the lower leg in association with acute spells of the what larger than ordinary lymphocytes and endowed intestinal disease. Now over 1 week a new lesion had with a large round nucleus and distinct nucleoli; these developed on the ventral aspect of the right lower leg. were probably stimulated lymphocytes. Adjacent to He used paracetamol, codeine, and temporarily sul- the affected vessel there was a vast granular necrosis fasalazine. in the dermis walled off by epithelioid cells, a few giant A biopsy specimen that included a large part of sub- cells, and lymphocytes (Fig. 14). cutaneous tissue was taken. It was investigated at sev- eral levels and stained with H&E, vG and PAS. In the subcutaneous tissue, close to the dermal–subcutane- 7.6.4 ous interface there was a large irregular abscess, which Comment merged into a vast and likewise irregular granular ne- The histopathologic pattern described in Case 13 crotic area. The latter mainly involved the subcutis, but (Fig. 7.13) was very much like that seen in subcutane- in some places reached into the dermis as long narrow ous vasculitis called erythema induratum when asso- strips. In several consecutive sections a “shadow” ves- ciated with tuberculosis and nodular vasculitis when sel with a totally necrotic wall was seen in the abscess. tuberculosis cannot be proved. The biopsy specimen Below the abscess a small artery, another part of the in this case probably displayed an unusually complete “shadow” vessel, was observed. In this segment the lu- picture of a lesion of granulomatous neutrophilic ar- men was obliterated by an erythrocyte thrombus, and terial vasculitis with widespread changes both in the the partly necrotic wall was permeated with disinte- subcutis and dermis. In Case 14 (Fig. 7.14) only a part grating neutrophils. In further sections the same vessel of an ascending arteriole tightly surrounded by epithe- displayed a wall with well-preserved smooth muscle lioid cells and lymphocytes was seen. The deep part of cells and only a partially occluded lumen. The necrotic the lesion, which presumably contained a neutrophilic areas in the dermis were surrounded by a rim of his- arterial vasculitis, was missing. tiocytes and epithelioid cells. Scattered small epithe- In recent years several case reports focusing on a lioid cell granulomas without necrosis were observed possible correlation between Crohn disease and gran- high in the dermis (Fig. 7.13). ulomatous skin lesions with or without vasculitis have appeared (Shum and Guenther 1990; Peltz et al. 1993; Case 14. Granulomatous Arterial Vasculitis Hackzell-Bradley et al. 1996). Also the vasculitis de- A 47-year-old master-builder was admitted because scribed in Category IV, neutrophilic arterial vasculi- of recurrent vasculitis-like lesions on the lower legs tis (so-called benign cutaneous periarteritis nodosa), which had been present for about 4 years. The lesions has been associated with Crohn disease (Daoud et al. remained for weeks or months, but never ulcerated. 1997; Gudbjörnsson and Hällgren 1990). However, if On admission he had some slightly reddened and ten- the investigated material is not complete or if the le- der nodules, 10-mm in diameter, located on the right sion is in regression the histopathologic diagnosis may lateral malleolus. Also, on both lower legs there were be difficult. Probably not all cases described as benign areas of brownish pigmentation, remnants of earlier periarteritis nodosa or nodular vasculitis are what nodules. On four occasions he had had gastrointes- they are said to be. tinal hemorrhage, probably due to duodenal ulcers. Routine laboratory values were normal. There was no evidence of systemic disease. The values for serum 7.7 complement factors were normal. Hepatitis B antigen Category VII: Mixed Group (Au antigen) was negative. Cryoglobulins were not In this heterogeneous group are included: erythema found. Direct immunofluorescence showed the pres- elevatum diutinum, granuloma faciale, angiolymphoid ence of IgG, IgA, IgM and C3 in material from both hyperplasia with eosinophilia (all three of unknown normal and affected skin. genesis), bacillary angiomatosis caused by Bartonella 7.7 Category VII: Mixed Group 51

Fig. 7.13 Granulomatous neutrophilic arterial vasculitis. a A botic branch (small arrow); H&E, ×300. c A necrotic area in the thrombotic small artery is located in a severely inflamed area in dermis is densely permeated by disintegrating neutrophils and the subcutis. The vessel wall is densely infiltrated by disintegrat- walled off by a brim of histiocytes and epithelioid cells; H&E, ing neutrophils; PAS, ×250. b The same vessel at another level. ×200. d A small epithelioid cell granuloma without necrosis lo- The wall of the vessel is preserved, but the lumen is obliterated cated in the upper half of the dermis; vG, ×300 (large arrow). In the left lower corner there is a small throm-

(Rochalimeae) henselae and a further case suspected scribed and named by Radcliffe-Crocker and Williams to be caused by an infectious agent. in 1894 (Laymon 1962). In the 1960s, case reports with reviews of the old literature were presented by among others Laymon (1962) and Mraz and New- 7.7.1 comer (1967). The following sections are in accor- Erythema Elevatum Diutinum dance with their descriptions of the disease and its Erythema elevatum diutinum (EED), which means natural course. protracted elevated erythema, is a rare disease, de- 52 7 Vasculitis

Fig. 7.14 Granulomatous arterial vasculitis. a The micrograph c Close-up of the lower part of the vessel in a. Lymphocytic cell shows an ascending arteriole, which can be followed from the infiltrate that, in addition to small lymphocytes, contains larger dermal–subcutaneous interface into the dermis (arrow heads); cells with a light nucleus and one or several nucleoli (stimulated vG, ×100. b Close-up of the upper part of the vessel in a. The lymphocytes). One arrow indicates one such cell, the other ar- vessel is embedded in a dense inflammatory cell infiltrate which row a mitotic figure in anaphase; PAS, ×600. d Part of the large consists of epithelioid cell granulomas with scattered giant cells necrotic area, which to the right is walled off by a granuloma- of Langhans type and lymphocytes (small arrows). At the large tous cell infiltrate arrowheads( ) including a giant cell of Lang- arrow a part of the thrombotic vessel is revealed; H&E, ×200. hans type (arrow); H&E, ×200 7.7 Category VII: Mixed Group 53

7.7.1.1 Two biopsy specimens were taken, one from the Clinical Appearance dorsal aspect of the hand and one from the face. They Both children and adults were affected, and, as the showed principally the same changes. The epidermis name indicates, the disease was chronic and the course was slightly hyperkeratotic but otherwise normal. In protracted. Histories of up to 10 years or more were the dermis dense patchy and partially coalescent in- described. Typically bluish-red or reddish-brown, in- flammatory cell infiltrates composed mainly of lym- filtrated papules and plaques were located symmetri- phocytes and histiocytes with admixture of plasma cally on the dorsal aspect of the hands, fingers, toes, cells and neutrophils were seen. There were many heels, knees, elbows and buttocks. Also the face could dilated vessels, both lymphatics and venules, and the be involved. The trunk and mucous membranes were latter often had protruding endothelial cells. In addi- rarely affected and vesicular and ulcerated lesions were tion there were scattered venules, some of which were unusual. New lesions appeared continuously. There thrombotic, other necrotic and permeated with nu- could be remissions and lesions could disappear, but clear fragments. The cell infiltrates around these ves- at the same time new papules poped up. Fibrotic tu- sels consisted mainly of lymphocytes and histiocytes. mor-like nodules could develop in patients with a long Eosinophils were not observed. There were also many disease duration. Usually patients did not complain of extravasated erythrocytes and a massive deposition of other symptoms than those from the skin. hemosiderin pigment (Fig. 7.15).

7.7.1.2 7.7.1.4 Histopathologic Appearance Comment Generally the tissue was profusely vascularized and In Case 15, both the clinical picture with chronic in- contained thick-walled venules with protruding endo- filtrates in acral areas and the histopathologic pattern thelial cells. However, some vessels were thrombotic with the notable mixture of marked chronic inflam- and/or displayed fibrinoid wall necrosis. There were mation and acute vascular damage are in accordance perivascular and dense patchy or confluent intersti- with those described as typical of EED in the old lit- tial inflammatory cell infiltrates composed of lym- erature. phocytes, histiocytes and neutrophils together with However during more recent years the criteria for nuclear fragments. In some areas lymphocytes and the diagnosis EED have changed. Katz et al. (1977) re- histiocytes dominated, in others neutrophils. In some ported on five cases believed to be EED and thereby specimens the number of neutrophils was conspicu- changed the criteria for the diagnosis. Thus they de- ous. Also, some eosinophils and plasma cells were clared that all early and most late lesions showed leu- noted. In tumor-like lesions the normal dermal archi- kocytoclastic angiitis associated with a dense dermal tecture was replaced by fibrotic tissue and contained infiltrate composed primarily of neutrophils and occa- patchy inflammatory cell infiltrates of neutrophils, sionally monocytes, though some late lesions showed a sometimes with nuclear fragments, but only a few ves- “fibrocytic” replacement of normal dermal structures. sels. The investigators were surprised to find acute vas- They found the histopathologic pattern of EED diffi- culitis in such a chronic disease as EED. cult to differentiate from that of leukocytoclastic vas- culitis. They based the diagnosis on the combination of the presence of leukocytoclastic vasculitis and the 7.7.1.3 clinical pattern (i.e., efflorescences distributed acrally Example and symmetrically over extensor surfaces). However, this distribution is characteristic also of leukocyto- Case 15. Erythema Elevatum Diutinum clastic vasculitis. Furthermore, these patients differed A 62-year-old male patient had suffered for a year from those in other reported series by having long his- from gradually enlarging and coalescent, reddish-blue tories of recurrent bacterial infections (prominently and rather thick, asymptomatic infiltrates on the dor- streptococcal) or by having other associated diseases sal aspect of the hands, fingers and toes, and on the (rheumatic fever, IgA monoclonal gammopathy). The chin and upper lip. He had no other complaints. At lesions disappeared dramatically when the patients a check-up 2 years later the described lesions were were treated with dapsone, but reappeared promptly mainly stationary, but brownish-blue, large, elongated after withdrawal of the drug. infiltrates had developed on the extensor area of the During the 1990s, there were an abundance of arti- elbows and forearms. cles on this rare disease associated with disorders such 54 7 Vasculitis

Fig. 7.15 Erythema elevatum diutinum. a, b Lesions on the chin, perivascular cell infiltrate consists mainly of lymphocytes. The upper lip and elbows. c In the dermis there are dense and con- dilated venule at the base has protruding endothelial cells. e fluent cell infiltrates and dilated thin-walled vessels. Thearrows Close-up of the lower vessel. It is totally necrotic and permeated indicate two affected venules. d Close-up of the area indicated by a mixed cell infiltrate and nuclear fragments. H&E by the upper arrow in c shows that the vessel is thrombotic. The

as IgA paraproteinemia, relapsing polychondritis, We- rically dispersed efflorescences on prominent parts of gener granulomatosis, celiac disease, and herpes virus the body. Mostly only a single biopsy specimen show- 6 infection (Yiannias et al. 1992; Bernard et al. 1992; ing unmitigated leukocytoclastic vasculitis was taken Kavanagh et al. 1993; Chow et al. 1996; Tasanen et al. before treatment. It follows that in these patients the 1997; Drago et al. 1999). In these cases, the diagnosis only proved diagnosis was leukocytoclastic vasculi- of EED was based on one or several spells of symmet- tis. However, it is interesting to note that in several of 7.7 Category VII: Mixed Group 55 these patients there was an association with IgA just as cells. Occasionally, fibrin deposition outside the vessel in Henoch-Schönlein purpura (Sect. 7.1.5.1). wall and even wall necrosis are noted. Extravasation of The cause of EED is not known, but it is thought to red blood cells is conspicuous. be a variant of classic leukocytoclastic vasculitis and thus presumably caused by circulating antigen–anti- body complexes (Lawley and Kubota 1990; Weedon 7.7.2.3 1997). However, there are important differences, clini- Pathogenesis cally as well as histopathologically, between these two The cause is unknown. Like EED, it is thought to be diseases. Leukocytoclastic vasculitis presents as an a variant of leukocytoclastic vasculitis, although there acute spell of lesions, which reaches a maximum and are important clinical as well as histopathologic differ- then declines and heals. As described in the old litera- ences. ture, EED starts insidiously and gives rise to remain- ing infiltrated papules and plaques, which at the same time reveal conspicuous chronic inflammation and 7.7.2.4 acute vasculitis with thrombotic/necrotic venules and Example nuclear fragments. Case 16. Granuloma Faciale A 39-year-old woman had noted for more than a year 7.7.2 a light-brown lesion in the right temporal area. It was Granuloma Faciale excised for cosmetic reasons. Granuloma faciale is a rare disease, but much more Histologic investigation revealed the above-de- common than EED. scribed pattern typical for granuloma faciale. There also were dilated venules with marginal vacuoles and numerous dilated lymphatics (Fig. 7.16). 7.7.2.1 Clinical Appearance It presents as one or several well-circumscribed, 7.7.2.5 brown, brownish-red, or bluish-red plaques localized Comment to the face. The lesion slowly enlarges and can become In this case several vessels with wall necrosis and de- several centimeters in diameter. It is a chronic, usu- position of fibrin were observed. In the author’s expe- ally asymptomatic and non-ulcerating condition. If rience these findings are rare, and may even be missing excised, it usually recurs. Extrafacial lesions have been in otherwise clinically as well as histopathologically described (Roustan et al. 1999). Usually, the patient is typical cases. middle aged. Males predominate.

7.7.3 7.7.2.2 Angiolymphoid Hyperplasia with Eosinophilia Histopathologic Appearance The concept angiolymphoid hyperplasia with eosino- The histopathologic pattern is highly characteristic. philia, also called histiocytic hemangioma by Rosai et Below the essentially normal epidermis there is a dis- al. (1979) and Rosai (1982), and epithelioid heman- tinct narrow zone that is free of inflammatory cells. In gioma by Fetsch and Weiss (1991), is confusing, and a the rest of the dermis and sometimes even in the su- review of the literature is necessary. perficial subcutaneous tissue there are dense, patchy, Wells and Whimster (1969) described nine pa- or confluent cell infiltrates, which encircle sebaceous tients with subcutaneous nodules in the head and glands and hair follicles without invading them. The neck region. Histologic investigation of early lesions cell infiltrates are polymorphic and composed mainly showed diffusely demarcated proliferation of vessels of lymphocytes and histiocytes with a rich admixture with protruding and vacuolated endothelial cells and of eosinophils and neutrophils. There are also some inflammatory cell infiltrates with many eosinophils, plasma cells and mast cells. Macrophages stored with while in older lesions lymphoid follicles with germi- hemosiderin pigment are found at all levels. Eosino- nal centers dominated. Other than blood eosinophilia, phils are diffusely scattered, while neutrophils and systemic symptoms were not observed. The course nuclear dust more often are found in aggregates and was benign, but often protracted and excised lesions close to dilated venules with protruding endothelial had a tendency to recur. It was regarded as a distinct 56 7 Vasculitis

Fig. 7.16 Granuloma faciale. a There is a dense, confluent cell infiltrate in the dermis with a narrow and nearly cell-free subepi- dermal zone. In addition there are many dilated venules, some of which have marginal vacuoles (arrow); ×125. b Close-up of the vessel indicated in a demonstrates vacuoles along the en- dothelium. The surrounding cells are mainly neutrophils; ×400. c A thin-walled dilated vessel with massive fibrin precipitates inside and outside the vessel wall (arrows). Here the dominating cells are lymphocytes; ×400. H&E

pathologic entity and named subcutaneous angiolym- veins and arteries as well as small vessels. Also in the phoid hyperplasia with eosinophilia (ALHE). Because investigation of Fetsch and Weiss (1991), including 96 of the presence of lymphoid follicles in older lesions patients with ALHE, most of the lesions were located of ALHE, the authors suggested an association with in subcutaneous fat tissue, in which a medium-sized Kimura disease, described in Japan in the 1940s (see artery or vein was affected. There is no agreement as Glossary). This is why Kimura disease and ALHE were to whether ALHE is a kind of benign tumor or a re- thought to be related diseases. Kandil (1970) reported active process, but the latter view prevails. A possible a patient with dermal nodules on the ear with a simi- relationship between Kimura disease and ALHE has lar histopathologic pattern as described by Wells and been strongly opposed by Rosai (1982) and Chun and Whimster (1969). The author thought his case to be Ji (1992). a cutaneous counterpart to subcutaneous ALHE, in- cluded similar previously reported cases (Peterson et al. 1964; Jones and Bleehen 1969), and called the 7.7.3.1 condition dermal ALHE. Thereafter the designation Example became ALHE and included subcutaneous as well as dermal lesions (Mehregan and Shapiro 1971). Rosai Case 17. Angiolymphoid Hyperplasia with et al. (1979) reported on ALHE and stressed that the Eosinophilia peculiar kind of vascular changes could also be found A 73-year-old woman presented with an erythema- in mucous membranes and bone and may affect large tous nodule which had been present for a month and 7.7 Category VII: Mixed Group 57 was located on the forehead; it was rounded and about Sangueza 1997). The background is a hypothesis that 10 mm in diameter. After 4 months of watching the le- during angiogenesis a new lumen is formed in the pro- sion, which had remained stationary, was excised. In a liferating string of endothelial cells due to intracellular telephone interview two and a half years later the pa- vacuolization followed by fusion of vacuoles in adja- tient said that she was well and that the lesion had not cent cells. However, today it is generally accepted that returned. the new lumen is formed between two abutting endo- The specimen was covered with a moderately ac- thelial outgrowths from the wall of the parent vessel anthotic but otherwise normal epidermis. The dermis and is probably an elongation of the parent vessel lu- was thickened and composed of loose, edematous men (Diaz-Flores et al. 1994). Investigations made by connective tissue, which contained dispersed col- Jones and Bleehen (1969) and Eady and Jones (1977) lagen bundles and different-sized, bizarre-looking, by light microscopy and enzyme histochemistry, cor- thick-walled venules. In a fully developed vascular le- related with electron microscopy, indicated that the sion the endothelium was prominent and composed vacuoles are empty (i.e., do not contain lipids or glyco- of large cells with condensed eosinophilic cytoplasm, gen) and that involved vessels are postcapillary venules and a large vesicular nucleus with a distinct nucleo- with a highly stimulated endothelium. The vacuolated lus. In scattered vessels one or two mitotic figures were endothelial cells are considered to be cells undergoing observed seemingly in the layer of cells just below the liquefaction degeneration (i.e. cells with intracellular endothelium. Many lumina were more or less filled edema; compare intracellular edema in keratinocytes up with large, empty PAS-negative vacuoles. Some of in Fig. 22.1a with those in Fig. 7.17b–d). these vacuoles were without any doubt situated in the In plain words, it seems likely that the vacuoles in cytoplasm of endothelial cells, which had a signet-ring the endothelial cells represent intracellular edema that appearance with a peripheral crescent-like nucleus. focally ends up in disintegration of the cells, which in The layer below the endothelium contained dispersed turn stimulates subendothelial cell proliferation and cells with vesicular nucleus and light indistinct cyto- results in thickening of the wall. This hypothesis favors plasm. This core was surrounded by several loosely the view that ALHE is a protracted reactive process arranged rings of thin collagen threads. Also thin- in response to some kind of continuous endothelial walled vessels had protruding endothelial cells, some injury, which may appear in different settings (Rosai of which were more or less filled with vacuoles. In 1982; Fetsch and Weiss 1991). One possibility is infec- longitudinally cut vessels of this type there were also tion caused by a so-far-unknown agent. It may be con- small areas where endothelial cells were missing or ap- sidered as a kind of chronic vasculitis. peared damaged and collapsed. Vascular wall necrosis and thrombosis were not seen. Engaged vessels were surrounded by different-sized, circumscribed, dense 7.7.4 inflammatory cell infiltrates composed mainly of eo- Bacillary Epithelioid Angiomatosis sinophils and lymphocytes with an admixture of his- Bacillary epithelioid angiomatosis (BEA) was first de- tiocytes, and plasma cells. Neutrophils were not seen. scribed only in patients with advanced HIV infection Lymphocytoma or lymphocytoma-like formations and was connected with cat-scratch disease. However, were not seen. The lesion was not sharply defined and intensive investigation has shown that the causative was not completely excised (Fig. 7.17). agent is Bartonella (Rochalimeae) henselae. This is a small rod-shaped organism which can be cultured and may be visualized in tissue by the silver staining 7.7.3.2 technique (Warthin-Starry, Steiner, and variants of Comment Steiner staining) (Cockerell 1995). BEA has also been The conspicuous vascular pattern with highly vacu- observed in patients not infected with HIV (Requena olated endothelial cells demonstrated in this case is and Sangueza 1997). well in accordance with what in the modern litera- Clinically small lesions could be taken for early Ka- ture is described as ALHE in the skin and elsewhere. posi sarcoma because of their bluish tint. Also histo- However, the significance of the vacuolated endothe- pathologically the two disorders share some features. lial cells is unclear. Rosai et al. (1979) postulated that They are both richly vascularized and have groups of the protruding and sometimes vacuolated endothelial proliferating vessels, often located close to hair fol- cells could represent primitive endothelial cells and licles and sweat glands, structures that are normally referred to embryonal angiogenesis, a view also sup- surrounded with a dense capillary network (Fig. 5.3a). ported in some of the modern literature (Requena and In both, the so-called promontory sign, a dilated lym- 58 7 Vasculitis

Fig. 7.17 Angiolymphoid hyperplasia with eosinophilia. a A which seem to originate from burst vacuoles; ×200. c Close-up dense inflammatory cell infiltrate obscures the dermis, in the of the vessel indicated in a. The lumen is obliterated by vacu- middle of which there are three affected vessels (arrows); ×100. olated endothelial cells with the signet-ring appearance. In the b The thick-walled vessels are embedded in a conspicuously subendothelial layer there are scattered large cells with a large edematous tissue that contains dispersed irregular collagen clear nucleus and a distinct nucleolus and two cells in mitosis, bundles. The vessel wall consists of three layers: endothelium, one in metaphase and one in prophase (arrows). The collagen a markedly edematous subendothelial layer, and an outer ring ring is diffusely penetrated by inflammatory cells; ×400. d A of thin collagen threads. At least two endothelial cells have large longitudinally cut, thin-walled vessel with vacuolated and partly intracytoplasmic vacuoles and the signet-ring appearance (ar- fused endothelial cells. The arrow indicates an endothelial cell rows). There are large marginal vacuoles in the lumen, some of containing small intracytoplasmic vacuoles; ×400. vG 7.7 Category VII: Mixed Group 59 phatic vessel containing a bud of connective tissue cided with doxycycline treatment for a spell of Pneu- which often contains one or several capillaries, may mocystis carinii pneumonia (Fig. 7.18). be observed (see Glossary). However, in BEA in the dermis there are densely packed thick-walled vessels Case 19. Mixed Venular Vasculitis of Unknown with epithelioid-like endothelium and dense infiltrates Cause of neutrophils, while in nodular Kaposi sarcoma there A 35-year-old woman discovered a small insect-bite- are densely packed bundles of spindle cells arranged like patch at the dorsal aspect of the left wrist on the in whirls. way home to Sweden from a visit to Portugal. The le- It is possible that an unknown infectious agent is sion slowly increased in size and she attended an out- the joker in other kinds of unusual skin lesions com- patient clinic for infectious diseases. Treatment with bined with mixed inflammatory cell infiltrates and oral penicillin was unsuccessful and she was referred mixed vascular changes. Case 19 may be such a case. to the Department of Dermatology. On the left fore- arm there was then a 50×70 mm well-demarcated le- sion with some central clearing and a slightly raised 7.7.4.1 erythematous margin and just inside the border zone a Examples scale collar. There were no pustules or vesicles. A simi- lar 10 mm patch without central clearing was seen on Case 18. Bacillary Epithelioid Angiomatosis her left shoulder. She was given topical treatment. For A 45-year-old man who suffered from AIDS with some time the lesion continued to slowly enlarge and spells of Pneumocystis carinii pneumonia had over scattered small new lesions appeared on the left arm 4 weeks developed 10 to 15 bluish-red, 2–3 mm ele- and also on the right forearm. However, about 7 weeks vated and slightly scaling papules on the abdomen and after the first patch was noted the two oldest lesions thighs. During the following 14 days the efflorescences begun to regress spontaneously and finally all lesions diminished, apparently spontaneously. However, over disappeared without further treatment. the following months the eruption became general- A biopsy specimen taken from the left wrist in- ized and some of the lesions enlarged. The latter had cluded the whole dermis and showed prominent a central crust or pustule encircled by a scale, which changes. In the upper and middle part of the dermis in turn was surrounded by an erythematous zone. The there were widespread coalescent inflammatory cell patient also had fever and an increased ESR. infiltrates which mainly consisted of neutrophils with Biopsy specimens from the early lesion and the later conspicuous leukocytoclasis. There also were many general eruption showed principally the same pattern eosinophils. In spite of the many nuclear fragments and included the dermal–subcutaneous interface. The only scattered small venules with fibrinoid wall necro- tissue was highly vascularized and contained large sis were observed. However, there were many dilated conglomerates of thick-walled venules with very high venules with protruding endothelial cells, some of epithelioid endothelial cells with scattered mitotic fig- which were filled with vacuoles and often surrounded ures. Some of these cells contained marginal empty mainly by lymphocytes. The epidermis was normal. PAS-negative vacuoles. Scattered venules were throm- There were no signs of folliculitis. Fungal structures botic. In addition many thin-walled dilated venules were not found. and lymphatics were observed. Between the thick- Laboratory investigations, including the blood, walled vessels especially there were dense aggregates of liver, urine, and electrophoresis, were normal with the neutrophils and nuclear fragments. In the surrounding exception of a slightly increased ESR, and increased tissue lymphocytes and fibroblasts dominated. Mast polyclonal IgG. Direct microscopy and culture for cells, but no plasma cells, were noted. There was no fungus were negative (Fig. 7.19). evidence of fungal infection. Unfortunately, the mate- rial was cut in series for a seminar; silver staining of the poor material remaining in the blocks showed the 7.7.5 tissue to be negative for bacteria. Comment The clinical appearance and the histopathologic In four of five of the cases described in Category VII, characteristics, as well as the disappearance of skin the occurrence of marginal vacuoles in vessel lumina lesions and general symptoms after treatment with was a prominent feature. Scattered marginal vacuoles erythromycin, verified the diagnosis bacillary epithe- in the lumen of both veins and arteries are now and lioid angiomatosis. In retrospect it was found that the then observed in seemingly normal vessels and are period of seemingly spontaneous amelioration coin- thought to be artifacts due to poor fixation (Majno 60 7 Vasculitis 7.8 Nomenclature 61

Fig. 7.19 Lesion, probably due to infection. a Well-circum- tissue with a dense inflammatory cell infiltrate composed of a scribed, erythematous lesion on the left forearm with active mixture of disintegrating neutrophils and lymphocytes. d A ne- margin and inside this a scale collar. b Fresh satellite lesion on crotic venule with perivascular fibrinous exudate and disinte- the left upper arm. c A dilated venule with protruding endo- grating neutrophils. H&E, ×400 thelial cells and vacuoles (arrow) is surrounded by edematous

and Joris 1996). However, the high number of both vacuolated endothelial cells and vacuoles in the vessel lumina in Case 17 give rise to the audacious thought that the vacuoles may be tombstones over disinte- grated endothelial cells and not artifacts.

Fig. 7.18 Bacillary epithelioid angiomatosis. a Three typical papular lesions. The papules have a scale collar and are sur- 7.8 rounded by an erythematous zone. b In the dermis there are Nomenclature densely packed epithelioid venules, separated by thin-walled and irregular vascular spaces (lymphatics). The arrow indicates A big problem concerning vasculitis is the synonym- a venule with marginal vacuoles; PAS, ×150. c Close-up shows rich and bewildering nomenclature. Sometimes the thick-walled venules surrounded by dense aggregates of neutro- designation is based on a clinical symptom, which is phils and nuclear fragments; H&E, ×400. d Arrowheads indicate not present in all cases with the same kind of histo- two parts of a horizontally running necrotic venule. The cell in- pathologic pattern, or also occurs in vasculitis with filtrate is mixed, but neutrophils and nuclear dust predominate; distinctly different histopathology. Some names are il- H&E, ×400. e The richly vascularized upper dermis in the right lusory, such as benign cutaneous polyarteritis nodosa lower corner shows a promontory sign; H&E, ×150. f Close-up and metastatic Crohn disease. Also a given designa- of the promontory sign. Thearrow indicates a capillary tion may have different meanings to different authori- 62 7 Vasculitis

ties. The situation is exemplified in the following para- a systemic disease, or the result of direct invasion of graphs. bacteria or virus. Lymphocytic venular vasculitis (like The distinct histopathologic pattern described here leukocytoclastic vasculitis) may be provoked by drugs, in Category IV as circumscribed leukocytoclastic arte- and is sometimes a component in the histopathologic rial vasculitis in deep dermis and subcutis is well doc- pattern of pityriasis lichenoides et varioliformis acuta. umented in the literature and by authorities such as Crohn disease has been associated both with granulo- Diaz-Peres and Winkelmann (1974), Lever and Scha- matous neutrophilic arterial vasculitis (Category VI) umburg-Lever (1990), and Weedon (1997) is called and with arterial neutrophilic vasculitis (Category IV). benign cutaneous poly- or periarteritis nodosa. How- The clinical pattern atrophie blanche may be caused ever, Ryan (1992), wanting to preserve the designation by different types of diseases. Furthermore, histologic polyarteritis nodosa for the systemic disease, called investigations of nodules on the lower legs with or it livedo with nodules, even though livedo is missing without livedo reticularis or ulcerations may reveal in many cases and ulceration is common in this type Category IV, V or VI vasculitis. It is therefore difficult of vasculitis (Daoud et al. 1997). Furthermore, livedo to make sensible classifications of vasculitis based on vasculitis is used synonymously with livedo with ul- causes, symptoms, or associated diseases. ceration, livedo reticularis with summer ulceration, It seems logical that the histopathologic features segmental hyalinizing vasculitis, and atrophie blanche should be the backbone in the labeling and classifi- (Ryan 1992). cation of different types of vascular lesions. To be of The clinical patternatrophie blanche is applied by value the investigation has to fulfill the following re- most authorities to spells of purpura and small ulcer- quirements: ations on the lower legs, ankles and dorsal aspects of • A fresh and non-ulcerated lesion should be chosen. the feet followed by whitish atrophic scars, pigmenta- An ulcerated lesion could be in organization (heal- tion, and sometimes livedo reticularis (Fig. 8.7a). The ing) and therefore lack significant characteristics or lesions are due to fibrinoid necrosis and/or thrombosis could be secondarily infected, which gives rise to a of venules and capillaries in the dermis. In some cases, variegated and confusing pattern. where the lesions have been called atrophie blanche or • The biopsy must include the whole dermis and a livedo vasculitis, hypercoagulability has been proved fair part of the subcutaneous tissue. The latter is (Pizzo et al. 1986; McCalmont et al. 1992). mandatory if the lesion is deep-seated. It is obvious that symptoms, such as livedo reticu- • The type of affected vessels and their location laris and the designation atrophie blanche, common to should be specified: small artery (subcutis), ascend- vascular lesions with a distinctly different histopatho- ing arteriole (subcutis, dermis), capillaries (dermis), logic pattern should not be used as diagnoses. Also, the postcapillary venules (dermis), or a vein (dermal/ acceptance of designations such as benign cutaneous subcutaneous interface, subcutis). Designations polyarteritis nodosa and metastatic Crohn disease im- such as medium-sized vessels and muscular vessels pedes one’s mind and prevents further development. do not give adequate information and are deceptive There are strong indications that systemic polyarteritis (Chapter 2). nodosa and so-called benign cutaneous polyarteritis • The type of inflammatory cells taking part and their nodosa are two different diseases. The mechanism extension should be specified. behind cutaneous manifestations of Crohn disease is • The presence of abscesses, necrotic areas and epi- not clear. The word metastatic implies vascular or lym- thelioid reactions should be noted. phatic spreading of either infectious agents or tumor However, from a histopathologic point of view the cells and therefore should be avoided. capacity of the tissue to respond to different kinds of stimuli is restricted. Therefore classification based on histopathology must be completed with investigations 7.9 at the molecular level. With few exceptions, knowledge Conclusion concerning mechanisms and pathways in vasculitis is The different kinds of vasculitis described above may incomplete. Presumably systematic, prospective inves- each be provoked by several different antigens, and tigations of vascular lesions based on the histopatho- may be expressed by different mechanisms (pathways). logic mapping described above, in combination with This means that one type of vasculitis could be a part immunohistochemical stainings designed to disclose of various skin diseases. For example, neutrophilic involved inflammatory cells (including subtypes), cy- venular vasculitis (leukocytoclastic vasculitis) can be tokines and CAMs will give further information. 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