Lipodermatosclerosis: a Clinicopathological Study of 25 Cases

Lipodermatosclerosis: A clinicopathological study of 25 cases

SarahN.Walsh,MD,andDanielJ.SantaCruz,MD St Louis, Missouri

Background: Lipodermatosclerosis is a chronic ﬁbrosing process that involves both lower legs and classically affects Caucasian women in their 60s.

Objective: The objective is to deﬁne the histologic spectrum seen this condition.

Methods: A total of 25 cases were collected prospectively and all were stained with hematoxylin-eosin, von Kossa, and Verhoeff-van Gieson.

Results: Patient age ranged from 33 to 84 years (mean age 62.6 years). The female to male ratio was approximately 12 to 1. All lesions were present on the lower extremities, between the knee and ankle. Lesion duration ranged from 2 months to 2 years (mean 9.5 months). Clinically, the lesions were erythematous, tender, indurated plaques or nodules. The characteristic histologic findings were seen almost exclusively in the subcutaneous tissue, involving primarily the lobules but also the septa. Adipose changes included micropseudocyst and macropseudocyst formation, necrotic adipocytes, lipomembranous change, and lipogranulomas with xanthomatous macrophages. The lesions were largely devoid of dermal, septal, or lobular neutrophilic or lymphocytic inflammation. Medium vessel calcification was seen in 13 cases. The accumulation of basophilic elastic fibers located deep in the septa was present in all the cases. These fibers had a moth-eaten appearance and resembled pseudoxanthoma elasticum. In 21 of 25 cases, these fibers were positive with both the von Kossa and Verhoeff-van Gieson stains.

Limitations: The cases in the series were not compared with age-, sex-, and location-matched biopsy specimens or biopsy specimens of other ﬁbrosing conditions.

Conclusion: This constellation of histologic changes is diagnostic of lipodermatosclerosis. The presence of pseudoxanthoma elasticumelike changes is a helpful, but not unequivocal, clue in this condition. ( J Am Acad Dermatol 2010;62:1005-12.)

Key words: hypodermitis sclerodermiformis; lipodermatosclerosis; pseudoxanthoma elasticum; sclerosing panniculitis; venous insufﬁciency.

ipodermatosclerosis, originally named is most commonly seen in obese Caucasian women ‘‘hypodermitis sclerodermiformis’’ and subse- in their 60s. Affected individuals are often smokers L quently termed ‘‘sclerosing panniculitis,’’ and typically have underlying vascular disease, rang- among others, is a chronic ﬁbrosing condition that ing from venous insufficiency to arterial ischemia. Although the cause may be multifactorial, the end From Cutaneous Pathology, WCP Laboratories Inc. result is constant and is characterized by painful Funding sources: None. indurated hyperpigmented plaques on the lower Conflicts of interest: None declared. extremities. Despite the consistent and well- The abstract to this series was presented as a poster at the United documented clinical findings, the microscopic States and Canadian Academy of Pathology Annual Meeting in changes have not been extensively detailed in the San Diego, CA on March 24-30, 2007. 1 Reprints not available from the authors. literature. Correspondence to: Sarah N. Walsh, MD, Cutaneous Pathology, WCP Laboratories Inc, 2326 Millpark Dr, St Louis, MO 63043. METHODS E-mail: [email protected]. 0190-9622/$36.00 The cases were collected prospectively from our ª 2009 by the American Academy of Dermatology, Inc. dermatopathology practice between September doi:10.1016/j.jaad.2009.08.006 1998 and December 2005. Multiple cuts of standard

1005 1006 Walsh and Santa Cruz JAM ACAD DERMATOL JUNE 2010 hematoxylin-eosinestained sections were was demonstrated by the presence of multinucleated examined. Von Kossa and Verhoeff-van Gieson giant cells acting on the necrotic adipocyte. The stains were performed on all cases. atrophic appearance was a result of fat necrosis and Patient demographics, lesion characteristics, and adipocyte dropout. Collections of foamy macro- differential diagnoses were gathered from the sub- phages were present, some forming lipogranu- mitted specimen reports and treating physicians. lomas (Fig 2, D). There was minimal, if any, chronic inflammation within the lobules, consisting RESULTS mainly of lymphocytes, The patients ranged in age plasma cells, and few eosin- from 33 to 84 years, with a CAPSULE SUMMARY ophils. Vasculitis was not mean age of 62.6 years. Of seen. Several cases showed d Consistent histologic findings of the 25 cases, there were 23 some degree of stasis within lipodermatosclerosis include lobular and women and two men the superficial capillary septal involvement of the subcutaneous (female: male ratio of ap- plexus of the papillary der- tissue, fat necrosis, macropseudocyst proximately 12:1). mis; otherwise, the dermis and micropseudocyst formation, and All lesions were present was relatively uninvolved. calcification of adipocytes. bilaterally on the lower ex- Verhoeff-van Gieson stains tremities with site specificity d Lipomembranes are classic but not highlighted the presence of as follows: lower leg (15), definitive for the diagnosis. abundant short frayed elastic ankle (6), calf (3), and shin d Pseudoxanthoma elasticum-like septal tissue within the septa, which (1). The known duration of elastosis with calcification is a consistent could be seen as basophilic the lesions ranged from 2 and helpful microscopic clue. fibers on hematoxylin-eosin months to 2 years, with a stain (Fig 3). Calcification of mean of 9.5 months. In 14 the abnormal elastic fibers cases, lesion duration was not available. was confirmed by positive staining with von Kossa, Clinically, the lesions were described as warm and in a pattern resembling pseudoxanthoma elasticum tender erythematous indurated, often hyperpig- (PXE) (Fig 4, A and B). In addition to calcification of mented, hard woody plaques and nodules (Fig 1). septal elastosis, there was also variable calcium depo- The clinical differential diagnosis was somewhat sition within the intima and media of medium blood limited, with lipodermatosclerosis being the most vessels, in the interstitium, in the walls of pseudocysts, common (9). Other diagnostic considerations, in and surrounding adipocytes (Fig 4, C and D). Soft order of frequency, were erythema nodosum (8), tissue ossification was noted in two cases (8%). panniculitis (6), stasis dermatitis (6), morphea (3), vasculitis (3), and one each of necrobiosis lipoidica, DISCUSSION atrophie blanche, diabetic dermopathy, lymphe- Lipodermatosclerosis is a disease process that dema, and squamous cell carcinoma. In 5 cases, clinically appears as erythematous indurated hyper- there were no clinical differential diagnoses pro- pigmented woody plaques occurring on the bilateral vided (Table I). lower extremities. Numerous other names have All specimens included the subcutaneous adipose been applied and proposed for this condition. tissue, with the type of procedure varying from ‘‘Hypodermitis sclerodermiformis’’ was the first to punch, incisional, or wedge biopsies to elliptical appear in the literature in 1955 as reported by Huriez excisions. On gross pathological examination, the et al,2 who described a scleroderma-like hardening specimens ranged in size from 0.3 3 0.3 3 0.4 cm to of the legs thought to result from infection of venous 1.8 3 0.6 3 0.9 cm; the average dimensions were ulcers. ‘‘Liposclerosis’’ was the name given by 0.6 3 0.4 3 0.7 cm. Browse et al3 in 1977 to the condition in which The histopathologic findings are summarized in patients with severe varicose veins developed thick- Table II. Microscopically, there was partial replace- ening, pigmentation, induration, and ultimately ment of the subcutaneous adipose tissue by fibrosis eczema and ulcers in the skin of the lower medial with widening of the septa. The adipose lobules third of the legs. In 1980, Burnand et al4 used the appeared both expanded and atrophic (Fig 2, A). term ‘‘venous lipodermatosclerosis,’’ which they The impression of expansion resulted from variably defined as ‘‘liposclerosis; the changes in the skin sized cystlike cavities, both large and small, within and subcutaneous changes commonly known as the adipose tissue (Fig 2, B). Many of the pseudocysts ‘postphlebitic leg.’’ ‘‘Sclerosing panniculitis’’ was had an eosinophilic scalloped feathery lining (Fig 2, proposed by Jorizzo et al5 in 1991 in an effort to C). Active formation of this crenulated membrane unify the designations of ‘‘hypodermitis JAM ACAD DERMATOL Walsh and Santa Cruz 1007 VOLUME 62, NUMBER 6

vascular damage, most notably, venous incompe- tence/hypertension and to a lesser extent arterial ischemia. Another key factor, for which treatment is often targeted, is abnormal fibrinolytic activity. Histologically, an increase in dermal fibroblast proliferation and procollagen gene expression have been noted on biopsy specimens of patients with lipodermatosclerosis in comparison with control subjects, suggesting that those factors are both involved in the development of the disease.8 A variety of medications and therapies have been tried, both singly and in differing combinations. These have included compression therapy with elastic bandages or stockings9; anabolic steroids9; topical, intralesional, and oral corticosteroids5,10,11; nonsteroidal anti-inflammatory drugs5; topical capsaicin12; antibiotics5; methotrexate5; pentoxifyl- line13; oral prostaglandin E11; tocopherol nicotin- ate11; ultrasound14; and surgical intervention.15 Although there are numerous options, there seems Fig 1. Classic clinical appearance of lipodermatosclerosis to be no universally accepted best form of treatment. with conﬂuent purple woody indurated plaques involving There have been reports discussing such clini- distal lower extremity. Honey crusted foci of ulceration are cally related aspects of the disease, from origin to also seen. (Courtesy of Jeffery Petersen, MD.) associations/risk factors to treatment, but little has been published regarding the histologic changes sclerodermiformis’’ and ‘‘lipodermatosclerosis.’’ that culminate in the diagnosis. We presented this ‘‘Stasis-associated lipomembranous panniculitis’’ series in 2007.1 Huang and Lee16 recently published was suggested by Snow and Su6 in 1996, who a histologic study of 17 cases of lipodermatoscle- thought this encompassed both the clinical and rosis, with an emphasis on distinguishing lipoder- histologic aspects of the disease. The term ‘‘pannic- matosclerosis from erythema nodosum. In their ulitis’’ literally means inflammation of the subcuta- report, lipodermatosclerosis was divided into 3 neous tissue. This process is primarily a fibrosing stages based on disease duration (acute =\1 month, condition with minimal, if any, inflammation. subacute = [1 month and \1 year, and chronic = Therefore, we prefer the designation of [1 year).16 Based on the chronological criteria ‘‘lipodermatosclerosis.’’ proposed in their report, our series, with known Despite the differing opinions on the most duration, would have 7 cases classified in the appropriate name for this entity, the clinical descrip- subacute stage and 4 in the chronic stage (none in tion has remained constant. The lesions are painful the acute phase). Similar to the subacute and and manifest as indurated erythematous hyperpig- chronic changes described in their series, we also mented plaques and nodules on the lower noted the presence of lipomembranes, cystic fat extremities. The underlying ﬁbrosis and lobular atro- necrosis, septal fibrosis, and venous stasis. phy give the impression of an inverted champagne However, there are no criteria for establishing the bottle with a hard, woodlike appearance which degree of these changes, making it difficult to becomes circumferential in well-developed lesions. correlate our results with theirs. In addition, we Occasionally there is overlying ulceration or crusting. did not see significant dermal or subcutaneous The exact origin is unknown although there are lymphocytic inflammation in any of our cases, many well-documented associations and risk factors. regardless of lesion duration, and we do not con- The disease is typically seen in Caucasians with a sider the presence of panniculitis to be a criterion striking predilection for women. Adults are uni- for lipodermatosclerosis. formly affected, with the sixth to seventh decade There is an apparent lack of information address- having the highest occurrence. In a 2002 study out of ing the histology of lipodermatosclerosis. The most the Mayo Clinic, 85% of the patients were overweight likely reason is that lipodermatosclerosis is fre- (body mass index [ 30) and 66% were obese (body quently not biopsied. One reason for this is the mass index [ 34).7 In addition, 59% were smokers.7 clinical appearance is often quite dramatic and dis- The most well-recognized association is with tinct and therefore the diagnosis can be made by the 1008 Walsh and Santa Cruz JAM ACAD DERMATOL JUNE 2010

Table I. Clinical findings in patients with lipodermatosclerosis

Case Age, y Sex Biopsy location Duration, mo Clinical diagnosis 1 59 F Lower leg 12 n/a 2 43 F Lower leg 12 EN 3 55 F Left ankle n/a LDS, EN, vasculitis 4 48 F Right calf 2 Panniculitis 5 81 F Left lower leg 2 Stasis dermatitis, panniculitis 6 72 F Left leg n/a n/a 7 84 F Left lower leg 2 n/a 8 75 F Right leg n/a EN, LDS 9 81 F Left lower leg 5 Diabetic dermopathy, stasis dermatitis, morphea, atrophie blanche 10 84 F Left ankle 6 EN, stasis dermatitis 11 71 M Left and right calves n/a n/a 12 59 F Left lower leg n/a Morphea, LDS 13 33 F Right shin n/a n/a 14 58 F Right ankle 6 EN, LDS 15 65 F Right ankle n/a EN, vasculitis 16 54 F Right lower leg n/a LDS 17 64 F Right lower leg 6 Stasis dermatitis, morphea, SCC 18 77 F Left ankle n/a Stasis dermatitis, vasculitis, panniculitis 19 71 F Left leg n/a Panniculitis, LDS 20 51 F Left ankle 24 EN 21 44 F Left lower leg n/a LDS 22 55 F Right lower leg n/a Lymphedema, LDS, EN 23 75 F Leg n/a Stasis dermatitis, panniculitis 24 52 F Right lower leg n/a Necrobiosis lipoidica 25 55 M Right calf 24 Panniculitis, LDS

EN, Erythema nodosum; F, female; LDS, lipodermatosclerosis; M, male; n/a, not available; SCC, squamous cell carcinoma. unaided eye rather reliably. However, other fibrosing showed lipomembranous change (96%) and calcifi- and inflammatory conditions can mimic lipoderma- cation of blood vessels (52%). tosclerosis, mainly morphea, erythema nodosum, Lipomembranes have a crenated appearance and erythema induratum, nephrogenic systemic fibrosis, are seen as an eosinophilic feathery anuclear lining scleromyxedema, and various forms of cellulitis of cystic adipocytes. They are thought to be caused and/or vasculitis. The distinction between such enti- by the interaction of residual products of disinte- ties becomes important, as treatment, response, and grated adipocytes and macrophages and may be a outcome can be different. A second reason is that result of ischemic injury to adipose tissue.18,19 diagnostic biopsy specimens need to be deep Lipomembranes are classic but not definitive for enough to include subcutaneous tissue, and such the diagnosis of lipodermatosclerosis and can be iatrogenic damage at the site can be slow to heal and found in numerous other conditions, mainly those may only complicate an already difficult-to-treat resulting from arterial ischemia or venous insuffi- condition.17 Finally, although lipodermatosclerosis ciency. In previous reports, lipomembranous fat is a well-recognized disease, it is rarely encountered necrosis was found in roughly decreasing order of on a daily basis. frequency, in erythema nodosum, morphea, trau- From our series, the combination of histologic matic panniculitis, lupus panniculitis, and necrobio- features that was the most reliable (found in all 25 of sis lipoidica among many others.4,16,18 In these the cases) was lobular and septal involvement of the studies, lipodermatosclerosis was the most common subcutaneous tissue, fat necrosis, macrocyst and diagnosis in which lipomembranes were identified. microcyst formation, calcification of adipocytes, In addition, when biopsy specimens of lipodermato- and septal elastosis. In addition, 84% of the cases sclerosis and erythema nodosum were compared, it had elastic fiber calcification in a pattern similar to was noted that the membranocystic fat necrosis in that seen in PXE. The majority of the cases also erythema nodosum consisted of small isolated foci JAM ACAD DERMATOL Walsh and Santa Cruz 1009 VOLUME 62, NUMBER 6

Table II. Histologic features seen in 25 cases of lipodermatosclerosis

Septal Fat Microcyst Lipomembranous Elastic tissue BV Fat Soft tissue Soft tissue Case involvement necrosis formation change Elastosis Ca11 Ca11 Ca11 Ca11 ossification 1 11 1 1 1111ÀÀ 2 11 1 1 11À 11 1 3 11 1 1 1111ÀÀ 4 11 1 1 11À 1 ÀÀ 5 11 1 1 11À 1 ÀÀ 6 11 1 1 1111ÀÀ 7 11 1 1 11À 1 ÀÀ 8 11 1 1 1111ÀÀ 9 11 1 1 1111ÀÀ 10 11 1 1 1111ÀÀ 11 11 1 1 1ÀÀ1 ÀÀ 12 11 1 1 1111ÀÀ 13 11 1 1 11À 1 ÀÀ 14 11 1 1 11À 1 ÀÀ 15 11 1 1 1111ÀÀ 16 11 1 1 11À 1 ÀÀ 17 11 1 1 1À 11 ÀÀ 18 11 1 1 1À 11 ÀÀ 19 11 1 1 11À 11 À 20 11 1 À 11111 À 21 11 1 1 1111ÀÀ 22 11 1 1 1111ÀÀ 23 11 1 1 11À 11 À 24 11 1 1 11À 1 À 1 25 11 1 1 1ÀÀ1 ÀÀ

BV, Blood vessel; Ca11, calcification. that were mainly located in the fibrous septa, often associated ABCC6 sequence alteration by genetic associated with radial granulomas, in contrast to the analysis.23 Therefore, it was suggested that the pres- prominent intralobular changes typically seen in ence of PXE-like fibers may be indicative of a subtle lipodermatosclerosis.16 Therefore, when one sees or subclinical PXE phenotype.23 However, many of lipomembranous fat necrosis, lipodermatosclerosis the biopsy specimens were from patients with un- should be the first consideration, recognizing that derlying fibrosing conditions, such as lipodermato- numerous other entities need to remain in the sclerosis. Given this and the fact that PXE-like fibers histologic differential diagnosis. had been previously noted in scars of patients with Septal elastosis was consistently present in lip- PXE, it was proposed that some fibrosing diseases odermatosclerosis. The vast majority of cases also may share similar cytokines with PXE that promote showed calcification of the elastic fibers with a formation of PXE-like fibers.23,24 Alternatively, PXE- somewhat moth-eaten appearance, similar to that like changes may be a degenerative or ‘‘aging’’ type seen in PXE. In addition to the primary disorder of phenomenon with no clinical or histologic signifi- PXE, this microscopic finding has been reported in cance. Confirmed by a von Kossa stain, we noted this other conditions, including calciphylaxis,20 nephro- PXE-like feature in more than three fourths of the genic systemic fibrosis,20 dermatomyositis,21 thalas- cases in our series (21/25, 84%). Similar to the semia,22 granuloma annulare,23 lichen sclerosus,23 lipomembranes, PXE-like changes of septal elastic morphea profunda,23 erythema nodosum,23 septal fibers are not specific for lipodermatosclerosis but panniculitis,23 basal cell carcinoma,23 and fibrosing are a helpful diagnostic clue. dermatitis not otherwise specified.23 We have also Blood vessel and adipocyte calcification were seen such changes in necrobiosis lipoidica and routinely noted on review of the von Kossa stains. occasionally in subcutaneous septa in patients with- The calcium deposits were present both within the out significant pathology in those areas, particularly inner and middle layers of the blood vessels. Medial in patients of advanced age. A recent report found calcification, particularly in the lower extremities of two of 6 patients with PXE-like fibers but without elderly patients, is characteristic of Mo¨nckeberg other evidence PXE to be heterozygous for the PXE- sclerosis. It is possible that the vascular calcification 1010 Walsh and Santa Cruz JAM ACAD DERMATOL JUNE 2010

Fig 2. Scanning magniﬁcation illustrates subcutaneous origin of disease as seen by thick ﬁbrous septa separating lobules of histologically abnormal adipose tissue with overlying unremarkable epidermis and dermis (A). Higher-power views of macropseudocyst and micropseudocyst formation with focal areas of lipomembranous change (B), close-up view of feathery crenated appearance of necrotic adipocyte (C), and fat necrosis with early formation of lipogranuloma (D). (A to D, Hematoxylin-eosin stain; original magnifications: A, 32; C and D, 340; B, 320.)

which is similar to the mean age of all patients within the series (62.6 years) and to the mean age of those with blood vessel calcification (64.7 years). Adipocyte calcification can also be seen in elderly patients and in such entities as calciphylaxis. In calciphylaxis, the accompanying distinctive blood vessel calcification is predominately in the small intralobular blood vessels as opposed to the medium vessels in our series. In lipodermatosclerosis, the vascular and adipocyte calcification are presumably related to the duration of the disease process and may not be seen in biopsy specimens of less established lesions. Soft tissue ossification was observed in a small number of cases, which may be a further manifestation of lesional age. Although Fig 3. Positively stained septal elastic fibers appear black. these features are nonspecific, they are characteristic (Verhoeff-van Gieson stain; original magnification: 32; of lipodermatosclerosis. inset, 310.) Even though lipodermatosclerosis is often a clinical diagnosis, it can appear similar to and be seen in our series could be secondary to age-related confused with other fibrosing and inflammatory arteriosclerosis. However, the mean age of those entities affecting the lower extremities. Although without blood vessel calcification was 60.4 years, there is no single feature on microscopic JAM ACAD DERMATOL Walsh and Santa Cruz 1011 VOLUME 62, NUMBER 6

Fig 4. At high magniﬁcation, short frayed basophilic elastic ﬁbers were noted within septa (A). Irregular patchy calcification of elastic tissue, reminiscent of pseudoxanthoma elasticum (B). Calcium is present in walls of medium blood vessels (C) and surrounding periphery of adipocyte (D), also highlighted by stain. (A, Hematoxylin-eosin stain; original magnification: 340. B to D, von Kossa stain; original magnifications: B, 310; C and D, 340.)

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