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ormal Subcutaneous Fat, Necrosis ofdipocytes and Classification of the Panniculitides

uis Requena, MD

The panniculitides represent a group of heterogeneous inflammatory diseases thatinvolve the subcutaneous fat. The specific diagnosis of these diseases requires his-topathologic study because different panniculitides usually show the same clinicalappearance, which consists of erythematous nodules on the lower extremities. How-ever, the histopathologic study of panniculitis is difficult because of an inadequateclinicopathologic correlation and the changing evolutive nature of the lesions. Inaddition, large scalpel incisional biopsies are required. From histopathologic point ofview, all panniculitides are somewhat mixed because the inflammatory infiltrate in-volves both the septa and lobules. However, nearly always the differential diagnosisbetween a mostly septal and a mostly lobular panniculitis is straightforward at scanningmagnification on the basis of the structures more intensely involved by the inflammatoryinfiltrate. Mostly septal panniculitides with vasculitis are actually more vasculitis thanpanniculitis and include superficial thrombophlebitis and cutaneous polyarteritis no-dosa. Mostly septal panniculitides with no vasculitis include erythema nodosum, necro-biosis lipoidica, deep morphea, subcutaneous granuloma annulare, rheumatoid nodule,and necrobiotic xanthogranuloma. Mostly lobular panniculitis with vasculitis is onlyrepresented by erythema induratum of Bazin. In contrast, mostly lobular panniculitideswithout vasculitis comprise a large series of disparate disorders, including sclerosingpanniculitis, calciphylaxis, sclerema neonatorum, subcutaneous fat necrosis of thenewborn, poststeroid panniculitis, lupus erythematosus profundus, pancreatic pannic-ulitis, �1-antitrypsin deficiency panniculitis, subcutaneous Sweet syndrome, infectivepanniculitis, factitial panniculitis, lipodystrophy, traumatic panniculitis, subcutaneoussarcoidosis, and sclerosing postirradiation panniculitis. Finally, some cutaneous lym-phomas may simulate panniculitis, both from clinical and histopathologic points of viewand, for that reason, they will be included in this review, although they are notinflammatory processes, but authentic lymphocytic neoplasms involving subcutaneoustissue.Semin Cutan Med Surg 26:66-70 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS panniculitis, subcutaneous fat, adipocytes, necrosis of the adipocytes

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he panniculitides are a group of heterogeneous in-flammatory diseases involving the subcutaneous fat.

lassically, the study of the panniculitides has been con-idered diagnostically challenging, both for dermatolo-ists and dermatopathologists, for several reasons. First,rom clinical point of view, the lesions show a disappoint-ng monotony, and very different processes involving the

epartment of Dermatology, Fundación Jiménez Díaz, Universidad Au-tónoma, Madrid, Spain.

ddress reprint requests to Luis Requena, MD, Department of Dermatology,Fundación Jiménez Díaz, Avda. Reyes Católicos 2, 28040-Madrid,

bSpain. E-mail: lrequena@fjd.es

6 1085-5629/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.sder.2007.02.001

ubcutaneous fat have the same morphology, presentings erythematous nodules generally located on the lowerimbs. In addition to this clinical unspecificity, the lesionsre located deep in subcutaneous tissue, and large exci-ional biopsies through subcutaneous fat must be per-ormed for diagnosis. From a histopathologic point ofiew, the panniculitides, like other inflammatory diseasesf the skin, constitute dynamic processes in which bothhe composition and the distribution of the inflammatorynfiltrate cells change within the course of a few days, andften biopsies are taken from late-stage lesions because ofnadequate clinicopathologic correlation. Usually, these

iopsies show nonspecific findings. Furthermore, some

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Introduction 67

uthorities believe that “the histologic septal-lobular di-hotomy is sometimes diagnostically useful, but more of-en there is a mixed picture that adds to interpretativeifficulties.”1

Despite all the aforementioned pitfalls, I think that, withn adequate biopsy and performing serial sections throughhe specimen, most times dermatopathologists may clas-ify the panniculitic process as a mostly septal or a mostlyobular panniculitis, and this classification system is veryelpful for initial diagnostic purposes. However, we mustecognize that this step is just the first one in the diagnostic

able 1 Classification of the Panniculitides

ostly septal panniculitidesith vasculitisVeinsArterieso vasculitisLymphocytes and plasma cells mostly

With granulomatous infiltrate in septaNo granulomatous infiltrate in septa

Histiocytes mostly: Granulomatous infiltrateWith mucin in center of palisaded granulomasWith fibrin in center of palisaded granulomasWith large areas of degenerated collagen, foamy histioc

and cholesterol cleftsWithout mucin, fibrin, or degeneration of collagen, but

radial granulomas in septa

ostly lobular panniculitidesith vasculitisSmall vessels

Venules

Large vesselsArteries:

o vasculitisFew or no inflammatory cells

Necrosis at the center of the lobuleWith vascular calcificationWith needle-shaped crystals in adipocytes

Lymphocytes predominantWith superficial and deep perivascular dermal infiltrateWith lymphoid follicles plasma cells and nuclear dust o

lymphocytesNeutrophils predominant

Extensive fat necrosis with saponification of adipocytesWith neutrophils between collagen bundles of deep ret

dermisWith bacteria, fungi or protozoaWith foreign bodies

Histiocytes predominant (granulomatous)No crystals in adipocytes:

With crystals in histiocytes or adipocytes

With cytophagic histiocytes

With sclerosis of the septa

rocess, and it should be followed by the search for addi-ional histopathologic findings that allow for a more spe-ific final diagnosis in the language of clinical dermatol-gy. Thus, the second step in the histopathologiciagnosis consists of assessing whether vasculitis isresent. If it is, the size and the nature of the involvedlood vessel should be determined. The third step must beo identify the nature of the cells that compose the inflam-atory infiltrate and, finally, to look for additional his-

opathologic features that allow a specific diagnosis of theisease involving the subcutaneous fat. Using this ap-

Superficial thrombophlebitisCutaneous polyarteritis nodosa

Necrobiosis lipoidicaDeep morphea

Subcutaneous granuloma annulareRheumatoid noduleNecrobiotic xanthogranuloma

Erythema nodosum

Erythema nodosum leprosumLucio phenomenon

Erythema induratum of Bazin

Sclerosing panniculitisCalciphylaxisSclerema neonatorum

Cold panniculitisLupus panniculitis (lupus erythematosus

profundus)

Pancreatic panniculitis�1-antitrypsin deficiency panniculitis

Infective panniculitisFactitial panniculitis

Subcutaneous sarcoidosisTraumatic panniculitisLipomembranous fat necrosisLipodystrophy and lipoatrophySubcutaneous fat necrosis of the newbornPoststeroid panniculitisCytophagic histiocytic panniculitisPanniculitis-like subcutaneous lymphomas

ytes,

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Sclerosing postirradiation panniculitis

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68 L. Requena

roach for diagnosis, Table 1 provides a working classifi-ation of the panniculitides.2,3

istology ofhe Subcutaneous Fatat tissue is widely scattered throughout the body, forming a

rue organ as regards to both structure and function.4 Subcuta-eous fat is organized into lobules of fat cells, also named lipo-ytes or adipocytes, and the lobules are separated by thin septaf connective tissue. The thickness of the subcutaneous fat variesrom one part of the body to another, with a thinner subcutis inreas of lax skin, such as the eyelids and scrotum, and thicker inhe hips and buttocks. There are also gender differences in theeposition of fat, and an increased thickness of the subcutisesults in the rounded contours of the female torso.

The adipocytes form a specialized part of the reticuloen-othelial system, and they are capable of fat synthesis and fattorage. Considered as individual cells, the adipocytes arearge, with a diameter up to 100 �m and, with hematoxylin–osin staining, appear as empty cells with signet-ring mor-hology. This appearance is attributable to the fact that theat spindle nucleus is displaced at the periphery of the cell bysingle, large intracytoplasmic vacuole, which contains fat.he septa that divide the subcutaneous fat into lobules are

hin and are composed of collagen and reticulin fibers. Theseepta house the blood and lymphatic vessels as well as theerves. Arteries and veins of the subcutis run along the septa.

able 2 Histopathologic Patterns of Fat Necrosis (Modifiedhite et al.6)

Adipocytes without nucleiGranular adipocytesLiquefactive fat necrosisHyalinizing fat necrosisMembranous fat necrosisMicrocystic fat necrosisIschemic fat necrosis

igure 1 Necrotic adipocytes. The nuclei are lacking. F

ach individual lobule is supplied by an arteriole branchingrom the septa to form capillaries into the lobule, and a cap-llary network surrounds each individual adipocyte. Postcap-llary venules meet in veins that also run along the septa. Inach microlobule, the arteriole occupies a central position,hereas the venule runs along the periphery. In contrast with

he dermal vascularization, the blood supply of each subcu-aneous microlobule is terminal, meaning there are no capil-ary connections between adjacent microlobules or betweenermis and subcutaneous fat. This peculiar structure of thelood supply in subcutaneous fat explains why large vesselasculitis involving the septal vessels usually is accompaniedy little inflammation of the fat lobules, whereas when theasculitis involves small blood vessels, there is extensiveecrosis of the adipocytes with centrilobular infarct andense inflammatory infiltrate within the lobule. The septa ofhe subcutaneous fat also contain a rich lymphatic plexus,hich come from the dermis and transverse the subcutis,rst, parallel to the surface of the skin and then verticallyenetrating the deep fascia and draining into the regional

ymph nodes.

igure 2 Lipophagic necrosis.

igure 3 Liquefactive fat necrosis.

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Introduction 69

A crucial histopathologic point in the study of panniculitisith large vessel vasculitis is to differentiate whether the in-olved vessel is artery or vein. A peculiarity of the veins in theubcutaneous fat of the lower limbs is that they often exhibitn “arterial” appearance because they have a thick muscularayer.5 However, with hematoxylin-eosin staining, the ve-ous nature of these vessels may be determined because theiddle layer of the subcutaneous veins is composed of sev-

ral muscular fascicles separated by tiny unstained elasticbers, whereas arteries show a more compact muscular layer.n classic pathology, many authors continue to promote theisleading notion that arteries of the subcutaneous fat of the

ower legs have a thicker muscular layer than veins, howeverhis is not necessarily true because often veins show thickeruscular layer than arteries. In difficult cases, elastic tissue

tain allows definite discrimination between artery and vein,ecause arteries show a well-formed, thick internal elastic

amina, whereas veins have a less evident internal elastic lam-na and show tiny elastic fibers interspersed between muscu-ar fascicles of the middle layer of the vessel wall.

igure 4 Hyalinizing fat necrosis.

igure 5 Membranous fat necrosis. F

ecrosis of the Adipocytesnother pitfall for histopathologic interpretation of pannicu-

itic biopsy specimens results from the fact that necrotic adi-ocytes exhibit different appearance from other necroticells.6 In classic histopathology, changes in nuclei, namely,yknosis, karyorrhesis, and kariolysis, are signs of cellularecrosis. In contrast, necrotic adipocytes, regardless of cause,ay appear as either anucleated cells or with complete dis-

ntegration of the cellular structure (Table 2).6

Sometimes the absence of nuclei is the only sign of necrosisf the adipocytes, and the fat cells appear as round emptyugs with no inflammatory infiltrate among them (Fig. 1).he most common type of fat necrosis is the so-called lipo-hagic necrosis, which consists of foamy macrophages ladenith the lipid products released from dead adipocytes. These

ipophages often exhibit a large, pale microvacuolated orranular cytoplasm (Fig. 2). Liquefactive fat necrosis is an-ther type of necrosis of adipocytes that produces granularisps of amphophilic detritus (Fig. 3). Hyalinizing fat necro-

is results in mummified adipocytes surrounded by glassyomogeneous proteinaceous material that effaces their archi-

igure 6 Microcystic fat necrosis.

igure 7 Ischemic fat necrosis.

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70 L. Requena

ecture (Fig. 4). Membranous fat necrosis is a late-stage ne-rosis of adipocytes that appears as a leathery eosinophilic ormphophilic rim of collapsed cellular organelles (Fig. 5).

hen membranous fat necrosis is extensive, fat microcystsevoid of cell structures appear (Fig. 6). Ischemic fat necrosis

s mostly seen at the center of the involved lobules and at

igure 8 Enzymatic fat necrosis.

rst the changes are subtle. However, in fully developed le-

ions, the involved adipocytes at the center of the lobuleppear as anucleated cells of a smaller size than normal adi-ocytes (Fig. 7). Later stages of ischemic necrosis are alsoharacterized by lipophagic necrosis. Enzymatic fat necrosiss caused by saponification of the adipocyte lipid contents byancreatic lipase, with secondary calcium salts deposition,esulting in ghost adipocytes, which show no nuclei andranular basophilic cytoplam (Fig. 8).

In this issue, we will present a comprehensive clinicopath-logic overview of the panniculitides. Emphasis will belaced on the characteristic histopathologic features for spe-ific diagnosis, and we will include short comments about thereatment for each entity.

eferences. Patterson JW: Panniculitis. New findings in the “third compartment.”

Arch Dermatol 123:1615-1618, 1987. Requena L, Sánchez Yus E: Panniculitis. Part I. Mostly septal panniculi-

tis. J Am Acad Dermatol 45:163-183, 2001. Requena L, Sánchez Yus E: Mostly lobular panniculitis. J Am Acad Der-

matol 45:325-361, 2001. Lundgren H, Bengtsson C, Blone E, Lapidus L: Adiposity and adipose

tissue distribution in relation to incidence of diabetic women. Int J Obes13:413-418, 1989

. Sanchez Yus E, Simon P, Sanz Vico D: ¿Vena o arteria? Una cuestióndecisiva en patología hipodérmica. Piel 2:213-217, 1987

. White WL, Wieselthier JS, Hitchcock MG: Panniculitis: Recent develop-

ments and observations. Semin Cutan Med Surg 15:278-299, 1996