in induratum of Bazin: A histopathologic study of 101 biopsy specimens from 86 patients

Sonia Segura, MD,a Ramo´nM.Pujol,MD,a Felicidade Trindade, MD,b and Luis Requena, MDb Barcelona and Madrid, Spain

Background: of Bazin is a mostly lobular . There is considerable controversy in the literature about whether or not vasculitis is a histopathologic requirement to establish the diagnosis of erythema induratum of Bazin. Even accepting vasculitis as a histopathologic criterion, there is no agreement about the nature and size of the involved vessels.

Objective: The main goal of our study was to investigate whether or not vasculitis was present in a large series of cases of erythema induratum of Bazin and, when vasculitis was found, to determine the nature and localization of the involved vessels.

Methods: We studied 101 skin biopsy specimens from 86 patients with clinicopathologic diagnosis of erythema induratum of Bazin. Histopathologic criteria required in each case to be included in this study were: (1) a mostly lobular panniculitis with necrotic adipocytes at the center of the fat lobule; (2) inflammatory infiltrate within the fat lobule mostly composed of neutrophils in early lesions and granulomatous infiltrate in fully developed lesions; (3) significant fat necrosis; and (4) absence of other histopathologic findings that allow a specific diagnosis of other lobular panniculitis different from erythema induratum of Bazin. We also recorded the nature of the inflammatory cells involving the fat lobule, and the lesions were classified into two main categories: (1) early lesions, when the inflammatory infiltrate was mainly composed of neutrophils, with or without leukocytoclasis; and (2) fully developed lesions, when histiocytes and lipophages were the predominant inflammatory cells within the involved fat lobule.

Results: Some type of vasculitis was evident in 91 cases (90.09%). A total of 47 biopsy specimens (46.5%) showed a mostly lobular panniculitis with necrotizing vasculitis involving the small vessels, probably venules, of the center of the fat lobule. Thirteen biopsy specimens (12.8%) showed a mostly lobular panniculitis with vasculitis involving both large septal veins and small vessels, probably venules, of the center of the fat lobule. Twelve biopsy specimens (11.8%) showed a mostly lobular panniculitis with vasculitis involving large septal veins, with no involvement or other septal or lobular vessels. Ten biopsy specimens (9.9%) showed a mostly lobular panniculitis with vasculitis involving large septal vessels, both arteries and veins, and necrotizing vasculitis involving the small vessels, probably venules, of the center of the fat lobule. Nine biopsy specimens (8.9%) showed a mostly lobular panniculitis with vasculitis involving large septal vessels, both arteries and veins, but with no involvement of the small blood vessels of the center of the fat lobule. Finally, 10 biopsy specimens (9.9%) showed a mostly lobular panniculitis without evidence of septal or lobular vasculitis in serial sections. Associated diseases included history of extracutaneous (including tuberculosis of the lung, lymph nodes, kidney, or bowel) in 12 cases (13.95%), previous episodes of superficial thrombophlebitis of the lower legs in 3 cases (3.72%), rheumatoid arthritis in one case (1.16%), Crohn disease in one case (1.16%), chronic lymphocytic leukemia in two cases (2.32%), hypothyroidism in two cases (2.32%), and positive serology for hepatitis B virus in 4 cases (4.65%) and for hepatitis C virus in 5 cases (5.81%).

From the Departments of Dermatology at Hospital del Mar, Correspondence to: Luis Requena, MD, Department of Universitat Auto´noma, Barcelona,a and Fundacio´n Jime´nez Dermatology, Fundacio´n Jime´nez Dı´az, Avda. Reyes Cato´licos Dı´az, Universidad Auto´noma, Madrid.b 2, 28040-Madrid, Spain. E-mail: [email protected]. Funding sources: None. 0190-9622/$34.00 Conflicts of interest: None declared. ª 2008 by the American Academy of Dermatology, Inc. Reprints not available from the authors. doi:10.1016/j.jaad.2008.07.030

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Limitations: Serial sections were not performed in all cases. At least 10 sections were studied in each case. When vasculitis was evident in some of these first 10 sections, no further sections were cut, but when histopathologic features of vasculitis were not found in the first 10 sections, serial sections throughout the specimen were performed looking for vasculitis. Because some type of vasculitis was evident in the first 10 sections of 91 cases, serial sections were performed only in the remaining 10 cases and they failed to demonstrate clear-cut histopathologic features of vasculitis. On the other hand, this is a retrospective study that was performed from the histopathologic slides of our files, and only the clinical information contained in the report accompanying the biopsy specimen could be recorded.

Conclusions: In our experience, vasculitis is present in most lesions of erythema induratum of Bazin, and the nature, location, and size of the involved vessels is, from more to less frequent, as follows: (1) small venules of the fat lobule; (2) both veins of the connective tissue septa and venules of the fat lobule; (3) only veins of the connective tissue septa; (4) veins and arteries of the connective tissue septa and venules of the fat lobule; and (5) veins and arteries of the connective tissue septa. However, in some cases with all clinicopathologic features of erythema induratum of Bazin vasculitis could not be demonstrated with serial sections throughout the specimen and, therefore, the presence of vasculitis should be not considered as a criterion sine qua non for histopathologic diagnosis of erythema induratum of Bazin. ( J Am Acad Dermatol 2008;59:839-51.)

Currently, the terms ‘‘erythema induratum of same entity,8,9 an opinion that we shared.10 Like Bazin’’ and ‘‘’’ are used as syno- , erythema induratum of Bazin is nyms by a majority of authors to describe the most currently considered to be a reactive disorder related common variant of mostly lobular panniculitides to several causative factors, one of which may be with vasculitis. This has not always been the case, tuberculosis, especially in some geographic areas.11 however. This form of panniculitis was originally In our country, tuberculosis is by far the most described by Bazin1 in 1861, as subcutaneous indu- important causative factor for erythema induratum rate erythematous plaques appearing mainly on the of Bazin, and recent polymerase chain reaction back of the lower aspect of legs of middle-aged investigations have demonstrated women. He classified the process as one of the tuberculosis DNA in 77% of the cutaneous biopsy erythematous benign scrofulids, using ‘‘scrofulids’’ specimens of patients with this variant of panniculi- as a descriptive term to refer to deep erythematous tis.12 Although the frequency varies from some nodules, and it seems that he did not consider this geographic areas to others, in many countries tuber- panniculitis as a tuberculid. The link between tuber- culosis is still the main causative factor for erythema culosis and erythema induratum was emphasized induratum of Bazin.13-20 In contrast, in those coun- later, around 1900, mostly by French dermatologists tries with low prevalence of tuberculosis, this type of who included erythema induratum within the spec- panniculitis may be a reactive process as a result of trum of the tuberculids.2 Almost simultaneously, other causative factors such as obesity, cold climate, identical clinical cases with no evidence of tubercu- chronic venous insufficiency, or history of thrombo- losis were reported by English authors,3,4 which led phlebitis of the lower limbs. later to the development of the concept of erythema Typical erythema induratum of Bazin is a disease induratum as nontuberculous in origin by Whitfield.5 of middle-aged obese women in whom erythema- In 1945, Montgomery et al6 in the United States tous subcutaneous nodules and plaques appear proposed the term ‘‘nodular vasculitis’’ for Whitfield on the back of the lower aspects of the legs. erythema induratum and described its clinical and Erythrocyanosis, heavy columnlike calves, erythema histopathologic features as different from those of surrounding follicular pores, and cutis marmorata erythema induratum of Bazin. Since then, most are frequently associated changes and may be textbooks of dermatology described erythema indu- predisposing factors. Although nonulcerated lesions ratum of Bazin, erythema induratum of Whitfield, may heal without scarring, often subcutaneous nod- and nodular vasculitis as 3 different entities.7 Still, ules become adherent to the skin surface and - some current authors have proposed keeping the ate. Healing of these ulcers is usually a slow process name ‘‘erythema induratum of Bazin’’ for those cases resulting in atrophic scars that allow retrospective in which a causative relationship with tuberculosis is diagnosis in nonactive cases. Erythema induratum of demonstrated and refer to the remainder of cases as Bazin is more frequent in obese women with some nodular vasculitis. In recent years, however, there degree of venous insufficiency of the lower extrem- seems to be a consensus considering erythema ities, and subcutaneous nodules with ulceration induratum of Bazin and nodular vasculitis as the develop mostly during the winter months. Lesions JAM ACAD DERMATOL Segura et al 841 VOLUME 59, NUMBER 5

Fig 1. Early lesion of erythema induratum of Bazin showing mostly lobular panniculitis with necrotizing vasculitis involving small vessels of center of fat lobule. A, Scanning power. B, Higher magnification showing mostly lobular panniculitis. C, Infiltrate of fat lobule was mostly composed of neutrophils. D, Necrotizing vasculitis involving small blood vessels of center of fat lobule. (A to D, Hematoxylin-eosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.) are usually tender but may be indolent or painful Controversy persists in the literature about whether only on pressure. The course is protracted and or not vasculitis is a histopathologic requirement to recurrent episodes over years, even decades, are establish the diagnosis of erythema induratum of common. Individual lesions tend to involute, but Bazin. Even accepting vasculitis as a histopathologic new crops appear at irregular intervals. Patients with criterion, there is no agreement about the nature of the erythema induratum of Bazin are otherwise in good involved vessel. Some investigators consider vasculi- health. tis as a characteristic histopathologic finding, but they From a histopathologic point of view, erythema fail to establish the nature and the size of the involved induratum of Bazin is a mostly lobular panniculitis. vessels.21 When the nature of the involved vessel is At an early stage, the fat lobules are punctuated specifically stated, some authors believe that they are throughout by discrete collections of inflammatory arteries,22,23 whereas other authors favor a venous cells, mostly neutrophils. There may be extensive involvement,24,25 and still others consider that both necrosis of the adipocytes of the fat lobule. These arteries and veins are involved.26-30 The main goal of necrotic adipocytes call for histiocytes that ingest our study was to investigate whether or not vasculitis lipid and become foamy. Epithelioid histiocytes, was always present in our cases of erythema indu- multinucleated giant cells, and lymphocytes contrib- ratum of Bazin and, when vasculitis was found, to ute to the granulomatous appearance of the in- determine the nature and localization of the involved flammatory infiltrate in fully developed lesions of vessels. This study also describes the histopathologic erythema induratum of Bazin. When intense vascular features of the largest published series of erythema damage is present, extensive areas of caseous ne- induratum of Bazin. crosis appear and the lesions show all the histopath- ologic attributes of a tuberculoid granuloma. METHODS Caseous necrosis may extend to the overlying dermis Skin biopsy specimens of 86 patients with clinico- and secondarily involve the epidermis with ulcera- pathologic diagnosis of erythema induratum of Bazin tion and discharge of liquefied necrotic fat. were retrieved from the archives of the departments 842 Segura et al JAM ACAD DERMATOL NOVEMBER 2008

Fig 2. Fully developed lesion of erythema induratum of Bazin showing mostly lobular panniculitis with necrotizing vasculitis involving small vessels of center of fat lobule. A, Scanning power. B, Higher magnification showing mostly lobular panniculitis. C, Granulom- atous infiltrate involving fat lobule. D, Necrotizing vasculitis of small blood vessels at center of fat lobule. (A to D, Hematoxylin-eosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.) of dermatology at Hospital del Mar, Barcelona, Spain From a histopathologic point of view, the follow- (22 biopsy specimens from 16 patients: 12 patients ing criteria were required to include each case in this with one biopsy specimen, 2 patients with two biopsy study: (1) a mostly lobular panniculitis with necrotic specimens, and 2 patients with three biopsy speci- adipocytes at the center of the fat lobule; (2) inflam- mens) and Fundacio´n Jime´nez Dı´az, Madrid, Spain matory infiltrate within the fat lobule mostly (79 biopsy specimens from 70 patients: 63 patients composed of neutrophils in early lesions and granu- with one biopsy specimen, 5 patients with two biopsy lomatous infiltrate in fully developed lesions; (3) specimens, and two patients with 3 biopsy speci- significant fat necrosis; and (4) absence of other mens). From a clinical point of view, all patients histopathologic findings that allow a specific diagno- showed characteristic cutaneous lesions, mostly sis of other lobular panniculitis different from consisting of erythematous nodules on the back of erythema induratum of Bazin. Other types of mostly the legs. Eighty patients showed positive cutaneous lobular panniculitis, including pancreatic panniculi- delayed hypersensitivity reaction to purified protein tis, alpha-1-antitrypsin deficiencyeassociated pannic- derivative (positive Mantoux test result), whereas 3 ulitis, sclerosing panniculitis, and lupus panniculitis patients showed negative Mantoux test result and this were ruled out on the basis of the histopathologic test was not performed in another 3 patients. Clinical findings. Infective panniculitis was ruled out when data were obtained from patient’s medical records Gram and periodic acideSchiff stains failed to dem- and, in each case, the demographic data, including onstrate micro-organisms in cases of a mostly neutro- age and sex, location of the lesions, and associated philic lobular panniculitis. Foreign body material was diseases, were recorded. ruled out throughout polarization in those cases of a JAM ACAD DERMATOL Segura et al 843 VOLUME 59, NUMBER 5

Fig 3. Early lesion of erythema induratum of Bazin showing mostly lobular panniculitis with vasculitis involving both large septal veins and small blood vessels of center of fat lobule. A, Scanning power. B, Higher magnification showing lobular panniculitis with neutrophilic infiltrate. C, Vasculitis involving large vein at septa. D, Necrotizing vasculitis involving small blood vessels at center of fat lobule. (A to D, Hematoxylin-eosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.) mostly lobular panniculitis with granulomatous of each case and, in selected cases, elastic tissue stain infiltrate. with orcein was performed to determine the nature Histopathologic criteria required to establish a of the vessels involved by vasculitis. At least 10 diagnosis of vasculitis included swelling of endothe- sections were studied in each case. When vasculitis lial cells, leukocytoclasis, fibrinoid changes in vessel was evident in some of these first 10 sections, no walls, and neutrophils in and around vessel walls. further sections were cut, but when histopathologic This vasculitis, the main goal of our study, was not features of vasculitis were not found in the first 10 initially considered as criterion sine qua non to sections, serial sections throughout the specimen include a case in this study when all other charac- were performed, looking for vasculitis. teristic histopathologic features of erythema indu- ratum of Bazin were present. However, because RESULTS vasculitis was evident in most cases, we recorded in Briefly, the clinical features of the 86 patients were all those cases the nature, size, and localization of the the following: 69 patients were female and 17 were involved blood vessel. We also recorded the nature male. Age ranged from 23 to 81 years (median 55.8 of the inflammatory cells involving the fat lobule, years). All patients showed erythematous subcuta- and the lesions were classified into two main cate- neous nodules in the back of the legs, and in 10 cases gories: (1) early lesions, when the inflammatory there were also some scattered erythematous nod- infiltrate was mainly composed of neutrophils, with ules on the front of the legs or on the thighs. Two or without leukocytoclasis; and (2) fully developed female patients also showed erythematous nodules lesions, when histiocytes and lipophages were involving the buttocks and one female patient had the predominant inflammatory cells within the in- lesions involving both the lower and upper limbs volved fat lobule. Skin biopsy specimens were fixed and the trunk. Most patients had new bouts of lesions in 10% buffered formalin, processed, and paraffin or worsening of pre-existing nodules during the embedded according to conventional techniques. winter. Associated diseases included history of Hematoxylin-eosin stain was performed in sections extracutaneous tuberculosis (including tuberculosis 844 Segura et al JAM ACAD DERMATOL NOVEMBER 2008

Fig 4. Fully developed lesion of erythema induratum of Bazin showing mostly lobular panniculitis with vasculitis involving both large septal veins and small vessels, probably venules, of center of fat lobule. A, Scanning power. B, Higher magnification showing lobular panniculitis with granulomatous infiltrate. C, Vasculitis involving large vein at septa. D, Necrotizing vasculitis involving small blood vessels at center of fat lobule. (A to D, Hematoxylin-eosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

of the lung, lymph nodes, kidney, or bowel) in 12 a mostly lobular panniculitis with vasculitis involving cases (13.95%), previous episodes of superficial both large septal veins and small vessels, probably thrombophlebitis of the lower legs in 3 cases venules, of the center of the fat lobule. This vasculitic (3.72%), rheumatoid arthritis in one case (1.16%), pattern was seen both in early lesions (5 cases [4.9%]) Crohn disease in one case (1.16%), chronic lympho- (Fig 3) and in fully developed lesions (8 cases [7.9%]) cytic leukemia in two cases (2.32%), hypothyroidism (Fig 4). Twelve biopsy specimens (11.8%) showed a in two cases (2.32%), and positive serology for mostly lobular panniculitis with vasculitis involving hepatitis B virus in 4 cases (4.65%) and for hepatitis large septal veins, with no involvement or other C virus in 5 cases (5.81%). septal or lobular vessels. This vasculitic pattern was Histopathologically, some type of vasculitis was seen both in early lesions (2 cases [1.9%]) (Fig 5) and evident in the first 10 sections of 91 cases (90.09%). In in fully developed lesions (10 cases [9.9%]) (Fig 6). the remaining 10 biopsy specimens (9.9%), serial Ten biopsy specimens (9.9%) showed a mostly sections failed to demonstrate clear-cut histopatho- lobular panniculitis with vasculitis involving large logic features of vasculitis. In all, 47 biopsy speci- septal vessels, both arteries and veins, and necrotiz- mens (46.5%) showed a mostly lobular panniculitis ing vasculitis involving the small vessels, probably with necrotizing vasculitis involving the small ves- venules, of the center of the fat lobule. This vasculitic sels, probably venules, of the center of the fat lobule. pattern was only seen in biopsy specimens of early There was no involvement of the septal vessels stages of erythema induratum of Bazin (Fig 7). Nine (small or large septal vessels). This vasculitic pattern biopsy specimens (8.9%) showed a mostly lobular was seen both in early lesions (with neutrophilic panniculitis with vasculitis involving large septal infiltrate in the fat lobule, 23 cases [22.7%]) (Fig 1) vessels (both arteries and veins), but with no in- and in fully developed lesions (with granulomatous volvement of the small blood vessels of the center of infiltrate within the fat lobule, 24 cases [23.7%]) the fat lobule. This vasculitic pattern was seen both (Fig 2). Thirteen biopsy specimens (12.8%) showed in biopsy specimens of early lesions (8 cases [7.9%] JAM ACAD DERMATOL Segura et al 845 VOLUME 59, NUMBER 5

Fig 5. Early lesion of erythema induratum of Bazin showing mostly lobular panniculitis with vasculitis involving large septal veins, with no involvement or other septal or lobular vessels. A, Scanning power. B, Higher magnification showing lobular panniculitis. C, Inflammatory infiltrate of fat lobule was mainly composed of neutrophils. D, Vasculitis involving large vein at septa. (A to D, Hematoxylin-eosin stain; original magnifications: A, 310; B, 340; C and D, 3200.)

(Fig 8) and in fully developed lesions (one biopsy developed lesions (8 cases [7.9%]) (Fig 10). From specimen [0.9%]). In all cases with some type of these 10 biopsy specimens without evidence of vasculitis (91 cases, 90.09%), vascular damage was vasculitis in serial sections, two biopsy specimens seen in all of the 10 performed sections, it was were from the same patient. Another 3 patients with located at the center of the panniculitic process (Figs two biopsy specimens showed septal large venous 1to8), and there was not any case in which vasculitis vasculitis in one biopsy specimen, but no evidence was identified without inflammation of the sur- of vasculitis was seen in the other one. The remain- rounding subcutaneous tissue. We did not find any ing 5 biopsy specimens without vasculitis belonged relationship between the presence of histologic to patients with only one biopsy specimen. Table I ulceration and the nature of the inflamed vessels, summarized the histopathologic features of our because histologic ulceration was evident only in 8 series. cases (7.9%), and two of them (1.9%) showed vas- culitis involving large arteries and veins of the septa DISCUSSION of the subcutaneous septa, whereas the remaining 6 In our experience, veins of the connective tissue ulcerated cases (5.94%) showed vasculitis involving septa and small venules of the fat lobule are the most the small blood vessels of the fat lobule without any common blood vessels affected by vasculitis in damage of the large arteries or veins of the connec- erythema induratum of Bazin, because 90.9% of tive tissue septa. Extravasated red cells were seen in our cases showed some type of venous vasculitis, the vicinity of the inflamed vessels in most cases. whereas arteries and arterioles were only involved in Finally, 10 biopsy specimens (9.9%), showed a 18.8% of the cases, and in all these cases with arterial mostly lobular panniculitis without evidence of sep- vasculitis, some type of venous vasculitis was con- tal or lobular vasculitis in serial sections and this comitantly identified. In other words, no case with pattern with no vasculitis was seen both in early exclusive arterial or arteriolar vasculitis was found in lesions (two cases [1.9%]) (Fig 9) and in fully our series. It was also remarkable that arterial and 846 Segura et al JAM ACAD DERMATOL NOVEMBER 2008

Fig 6. Fully developed lesion of erythema induratum of Bazin showing mostly lobular panniculitis with vasculitis involving large septal veins, with no involvement or other septal or lobular vessels. A, Scanning power. B, Higher magnification showing lobular panniculitis. C, Granulomatous inflammatory infiltrate involving fat lobule. D, Vasculitis involving large vein at septa. (A to D, Hematoxylin-eosin stain; original magnifications: A, 310; B, 340; C and D, 3200.) arteriolar vasculitis was mostly seen in biopsy spec- erythema induratum of Bazin may show all classic imens with a predominant neutrophilic infiltrate clinicopathologic features of the disorder, except involving the fat lobule (there was only one case vasculitis, and thus the term ‘‘erythema induratum of with involvement of both large arteries and veins of Bazin’’ is more accurate than ‘‘nodular vasculitis’’ to the septa and granulomatous infiltrate at the fat name this process. lobule), which probably indicates that involvement A review of the literature and of the most famous of arterial vessels of the subcutaneous fat is only textbooks of dermatology and dermatopathology present in early stages of the evolution of the lesions. reveals considerable variation about whether or not Curiously enough, in 10 biopsy specimens of this vasculitis is present in the cutaneous lesions of series, which showed all stereotypical clinicopatho- erythema induratum of Bazin. Even in those cases logic features of erythema induratum of Bazin, serial in which vasculitis is accepted by the investigators as sections throughout the specimens failed to identify a characteristic histopathologic feature, controversy clear-cut histopathologic features of vasculitis. exists about the size, the nature, and the location of Furthermore, in one patient of our series, who the involved vessels. Thus, in some textbooks, vas- showed all classic clinicopathologic features of ery- culitis is described as a characteristic histopathologic thema induratum of Bazin, two biopsies were finding of erythema induratum of Bazin, but the performed from two separate episodes of the pan- nature, size, and location of the involved vessels are niculitic process and no evidence of vasculitis was not established.21 Ackerman22 believes that ‘‘nodular found in either of the two biopsy specimens, vasculitis is so named because clinically the lesion is a whereas another 3 patients with two biopsy speci- nodule, and microscopically it is an arteritis. This mens showed vasculitis of the large septal veins in severe vasculitis, in which neutrophils, lymphocytes, one biopsy specimen, but no histopathologic fea- and histiocytes participate, involves a muscular arte- tures of vasculitis could be identified in the other ria and eventuates in ischemic changes within one. Therefore, although rare, some cases of the lobule or portions of the lobules supplied by JAM ACAD DERMATOL Segura et al 847 VOLUME 59, NUMBER 5

the affected artery.’’ In our opinion, however, the involved vessel illustrated by Ackerman22 as an example of nodular vasculitis (erythema induratum of Bazin) is better interpreted as a vein rather than as an artery. In our view, this is a frequent mistake in the histopathologic study of the panniculitides and vas- culitides involving the subcutaneous fat of the lower legs, because in these areas the veins of the connec- tive tissue septa of the subcutis show a thicker and more compact muscular layer than the veins of the subcutis in other areas of the skin and they often are misinterpreted as arteries.23 Black,24 in agreement with Ackerman,22 also considers that arteries are the vessels mainly involved in the lesions of erythema induratum of Bazin. In contrast, Degos,25 in his textbook of dermatology, considered that erythema induratum of Bazin is a mostly lobular panniculitis with vasculitis mainly involving the veins of the connective tissue septa of the subcutis. A venous vasculitis is also postulated by McKee et al26 in their last edition of Pathology of the Skin, because they wrote: ‘‘The histologic features [of nodular vasculitis] combine septal and lobular changes with the pres- ence of vasculitis being a sine qua non (Fig. 9.79). In a biopsy from an established lesion, the septa are widened and chronically inflamed (Fig. 9.80). Acute vasculitis, affecting veins and venules with a heavy inflammatory cell infiltrate consisting of neutrophils, lymphocytes and histiocytes is typically present, sometimes accompanied by vessel wall necrosis and thrombosis.’’ McKee et al26 failed to establish the location of the involved vessels, but because they considered that both veins and venules were in- volved, we deduce that they interpreted that the venous vessels of both the connective tissue septa and the fat lobule were involved. Patterson27 consid- ered that ‘‘vasculitis is frequently present and can involve small or medium-size vessels (Fig. 100.8). It may be predominantly neutrophilic, lymphocytic or granulomatous,’’ but he did not establish whether the involved vessels were arterial or venous, or whether the vasculitic process involved the septa, the fat lobule, or both. Other authors believe that both venous and arterial blood vessels are involved in Fig 7. Early lesion of erythema induratum of Bazin lesions of erythema induratum of Bazin, but discrep- showing mostly lobular panniculitis with vasculitis involv- ancy still persists about the size of the vessels, ing large septal vessels, both arteries and veins, and because whereas some of them considered that large necrotizing vasculitis involving small vessels of center of veins and arteries are affected,28 others stated that fat lobule. A and H, Scanning power. B and I, Mostly lobular panniculitis with involvement of large vein of septa. C and J, Higher magnification showing vasculitis Necrotizing vasculitis involving small blood vessels at involving large vein of septa. D and K, In other areas with center of fat lobule. (A to G, Hematoxylin-eosin stain; lobular panniculitis vasculitis involved arteries of septa. E original magnifications: A, 310; B and D, 340; C, E, and F, and L, Higher magnification showing involvement of 3200; G, 3400. H to L, Elastic tissue stain; original septal artery. F, Neutrophilic infiltrate in fat lobule. G, magnifications: H, 310; I and K, 340; J and L, 3200.) 848 Segura et al JAM ACAD DERMATOL NOVEMBER 2008

Fig 8. Early lesion of erythema induratum of Bazin showing mostly lobular panniculitis with vasculitis involving large septal vessels, both arteries and veins, but with no involvement of small blood vessels of center of fat lobule. A, Scanning power. B, Involvement of both artery and vein of septa. C, Involved artery shows intense fibrinoid necrosis of tunica intima. D, Despite intense fibrinoid necrosis of artery, internal elastic membrane is still discernible. (A to D, Hematoxylin-eosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

only small and medium arteries and veins are in- showed features of neutrophilic vasculitis. Necrosis volved,29 and finally others described involvement of of the adipocytes and inflammatory response were all sizes of arteries and veins.30 Curiously, even within more intense in type II.33 In our opinion, this the same textbook, there are discrepancies between classification is difficult to apply in a particular different chapters, because in a textbook edited by case, because the intensity of inflammation of the Farmer and Hood, Pathology of the Skin, Olsen31 fat lobules often varies from one lobule to another considered in the chapter of vasculitis that nodular within the same biopsy specimen. Furthermore, in vasculitis was ‘‘a panarteritis involving a small to our experience this system of classification is not of medium-sized artery, typically in the subcutis,’’ practical use, because in the cases that we are whereas Dahl and Su,32 in their chapter of pannicu- reporting in this series we did not find correlation litis, dealing with erythema induratum of Bazin- between the intensity of inflammatory infiltrate nodular vasculitis, described that ‘‘vasculitis, usually within the fat lobule and the number, size, nature, lymphohistiocytic, involves venules, veins, and even and location of the involved blood vessels of the arterioles and small arteries in the pannicular septae.’’ subcutis. Moreover, in some cases of erythema In a recent series of 20 patients with erythema induratum of Bazin with all the stereotypical clini- induratum of Bazin-nodular vasculitis, the lesions copathologic features of erythema induratum of were histopathologically classified into two types: Bazin-nodular vasculitis, serial sections throughout focal panniculitis (type I) and diffuse panniculitis the block of a subcutaneous nodule did not demon- (type II). In type I erythema induratum of Bazin- strate findings of vasculitis. Therefore, we do not nodular vasculitis, only one artery or a small blood consider vasculitis as a sine qua non criterion to vessel within the fat lobule was involved by neutro- establish the diagnosis of erythema induratum of philic vasculitis. In type II erythema induratum of Bazin when other characteristic findings are present. Bazin-nodular vasculitis, several blood vessels of Another major problem in dealing with small different sizes both in the septa and the fat lobule blood vessel vasculitis in the context of neutrophilic JAM ACAD DERMATOL Segura et al 849 VOLUME 59, NUMBER 5

Fig 9. Early lesion of erythema induratum of Bazin. Serial sections failed to demonstrate vasculitis. A, Scanning power. B, Higher magnification showing mostly lobular panniculitis. C, Inflammatory infiltrate of fat lobule was mostly composed of neutrophils. D, Still higher magnification showing neutrophils and some nuclear dust, but no evidence of vasculitis. (A to D, Hematoxylin-eosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.) lobular panniculitis is the question of whether or not pathogenic role in the process and the vascular the vascular injury is primary. Cutaneous vasculitis collateral damage is caused by a nonvasculitic insult can be classified into primary, secondary, or inci- to the vessels. Inflammation is not directed at the dental.34 Primary vasculitis is idiopathic and implies vessel, but the vessels are damaged because they are that the vascular insult is the predominant patho- in the vicinity of the insult.34 In this sense, it might be genic factor in the process. Examples of primary interpreted that the leukocytoclastic vasculitis in- cutaneous vasculitis include most cases of cutaneous volving the small blood vessels of the fat lobule seen leukocytoclastic vasculitis, polyarteritis nodosa, in early lesions of erythema induratum of Bazin with giant cell arteritis, and antineutrophilic cytoplasmic a mostly neutrophilic infiltrate within the fat lobule antibodyepositive vasculitis syndromes, including was a secondary infective vasculitis as a result of M Wegener granulomatosis, Churg-Strauss syndrome, tuberculosis or even an incidental vasculitis within a and microscopic polyangiitis. In contrast, secondary neutrophilic infiltrate. However, there are several vasculitis is caused by and part of a known disease, features that militate against these possibilities. and although inflammation is also directed at vessel Concerning infective vasculitis, M tuberculosis has wall constituents, there is one more process in wider, been demonstrated by polymerase chain reaction often inflammatory syndromes. Secondary cutane- techniques in cases of erythema induratum of Bazin ous vasculitic syndromes include lupus of some countries, but not in cases from other erythematosus vasculitis, rheumatoid vasculitis, ma- geographic areas and, if the process is the same in lignancy-induced vasculitis, infection-induced vas- all areas,8-10 another pathogenic factor besides M culitis, and drug-induced vasculitis. Finally, tuberculosis must be involved in the process. Finally, incidental vasculitis refers to focal vasculitis found the vasculitic process involving the small blood within a predominantly neutrophilic infiltrate, such vessels of the fat lobules in most of our cases of as in venous ulcers of the lower legs or in early erythema induratum of Bazin can not be interpreted lesions of herpes simplex and herpes zoster, and it is as an incidental vasculitis. First of all, necrotizing accepted that this incidental vasculitis has no leukocytoclastic vasculitis of the small blood vessels 850 Segura et al JAM ACAD DERMATOL NOVEMBER 2008

Fig 10. Fully developed lesion of erythema induratum of Bazin. Serial sections failed to demonstrate vasculitis. A, Scanning power. B, Higher magnification showing mostly lobular panniculitis. C, Granulomatous infiltrate involving fat lobule. D, Higher magnification of histiocytic infiltrate with no evidence of vasculitis. (A to D, Hematoxylin-eosin stain; original magnifications: A, 310; B, 340; C, 3200; D, 3400.)

Table I. Type of involved vessels in vasculitis in 101 biopsy specimens from 86 patients with erythema induratum of Bazin

Lobular venules 1 Lobular venules 1 septal veins 1 Septal veins 1 Lobular venules septal veins Septal veins septal arteries septal arteries No vasculitis 47 Cases (46.5%) 13 Cases (12.8%) 12 Cases (11.8%) 10 Cases (9.9%) 9 Cases (8.9%) 10 Cases (9.9%) (All cases were EL) - EL: 23 cases - EL: 5 cases - EL: 2 cases - EL: 8 cases - EL: 2 cases (22.7%) (4.9%) (1.9%) (7.9%) (1.9%) - FDL: 24 cases - FDL: 8 cases - FDL: 10 cases - FDL: 1 case - FDL: 8 cases (23.7%) (7.9%) (9.9%) (0.9%) (7.9%)

EL, Early lesions (mostly neutrophilic infiltrate); FDL, fully developed lesions (mostly histiocytic infiltrate). was seen not only in early lesions of our series, but common type of vasculitis seen in biopsy specimens also in many biopsy specimens from fully developed of erythema induratum of Bazin has pathogenic lesions with a predominantly granulomatous infil- significance and it must be considered as primary trate involving the fat lobule. Second, besides ery- vasculitis. thema induratum of Bazin, there are several other In conclusion, although there is no consensus panniculitic processes with a predominantly neutro- about the nature, size, and location of the involved philic infiltrate within the fat lobule, such as neutro- vessels in erythema induratum of Bazin, on the basis philic lobular panniculitis or subcutaneous Sweet of the findings of this series, we consider vasculitis as syndrome, pancreatic panniculitis, alpha-1-antitryp- almost always present in lesions of erythema indu- sin deficiencyeassociated panniculitis, infective pan- ratum of Bazin, and the nature, location, and size of niculitis, and factitial panniculitis, which do no show the involved vessels is, from more to less frequent, as leukocytoclastic vasculitis of the small blood vessels follows: (1) small venules of the fat lobule; (2) both of the fat lobule.35 Therefore, we think that the most veins of the connective tissue septa and venules of the JAM ACAD DERMATOL Segura et al 851 VOLUME 59, NUMBER 5

fat lobule; (3) only veins of the connective tissue 15. Schneider JW, Geiger DH, Rossouw DJ, Jordaan HF, Victor T, septa; (4) veins and arteries of the connective tissue van Helden PD. Mycobacterium tuberculosis DNA in erythema septa and venules of the fat lobule; and (5) veins and induratum of Bazin. Lancet 1993;342:747-8. 16. Schneider JW, Jordaan HF, Geiger DH, Victor T, van Helden PD, arteries of the connective tissue septa. Because some Rossouw DJ. Erythema induratum of Bazin: a clinicopathologic type of vasculitis is seen both in early and fully study of 20 cases and detection of Mycobacterium tuberculosis developed lesions and because vasculitis is more DNA in skin lesions by polymerase chain reaction. Am J consistently present in lesions of erythema induratum Dermatopathol 1995;17:350-6. of Bazin than in other mostly lobular panniculitis, we 17. Lopez-Estebaranz JL, Iglesias Diez L. 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