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Anatomy and Histology of Normal Subcutaneous Fat, Necrosis of Adipocytes, and Classification of the Panniculitides
Anatomy and Histology of Normal Subcutaneous Fat, Necrosis of Adipocy tes, and Classification of the Panniculitides Sonia Segura, MDa,*, Luis Requena, MDb KEYWORDS Panniculitis Subcutaneous fat Adipocytes Necrosis of the adipocytes
of the inflammatory infiltrate cells change within the course of a few days, and often biopsies are taken from late-stage lesions because of inadequate clinicopathologic correlation and they show nonspecific findings. Some authorities believe that ‘‘the histologic septal-lobular dichotomy is sometimes diagnostically useful, but more often there is a mixed picture that adds to interpretative difficulties.’’1 Despite these pitfalls, the authors believe that with an adequate biopsy and performing serial sections through the specimen, dermatopathologists may classify the panniculitic process as a mostly septal or a mostly lobular panniculitis, and this classification system is very helpful for initial diagnostic purposes. This is just the first step in the diagnostic process, however, and it should be followed by the search of additional histopathologic findings that allow a more specific final diagnosis in the language of clinical dermatology. The second step in the histopathologic diagnosis deals with the assessment of whether vasculitis is or is not present, and when it is present the nature of the involved blood vessel should be determined. Finally, the third diagnostic step is the identification of the nature of the cells that compose the inflammatory infiltrate and the search for additional
a
Department of Dermatology, Hospital del Mar, IMAS, Passeig Marı´tim 25-29, 08003 Barcelona, Spain Department of Dermatology, Fundacio´n Jime´nez Dı´az, Universidad Auto´noma, Avda. Reyes Cato´licos 2, 28040, Madrid, Spain * Corresponding author. E-mail address: [email protected] (S. Segura). b
Dermatol Clin 26 (2008) 419–424 doi:10.1016/j.det.2008.05.011 0733-8635/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
derm.theclinics.com
The panniculitides comprise a heterogeneous group of inflammatory diseases involving the subcutaneous fat. These disorders have been classically considered diagnostically challenging, both for dermatologists and dermatopathologists, for several reasons. First, from a clinical point of view, dermatologists are used to evaluating different morphologic aspects of the altered skin to render a diagnosis, but subcutaneous tissue is not visible to examining eye. Instead, the lesions usually show a disappointing monotony, and entirely disparate diseases involving the subcutaneous fat appear with the same morphology, which consists of erythematous nodules, mostly located on the lower limbs. Second, the lesions are situated deep in subcutaneous tissue and large excision biopsies through subcutaneous fat must be performed for diagnosis to evaluate correctly the pattern of the inflammatory cell infiltrate and the involvement of blood vessels. Third, from a histopathologic point of view, the subcutaneous fat responds to a variety of insults in a limited number of forms, and pathologic differences between some of the conditions are sometimes subtle. Moreover, the panniculitides, like other inflammatory diseases of the skin, are dynamic processes in which both the composition and the distribution
420
Segura & Requena histopathologic features that allow a specific diagnosis. Box 1 provides a working classification of the panniculitides using this approach for diagnosis.2,3
ANATOMY AND HISTOLOGY OF THE SUBCUTANEOUS TISSUE Subcutaneous tissue is widely scattered throughout the body, forming a true organ as regards both structure and function.4 This tissue is crucial for thermal regulation, insulation, provision of energy, and protection from mechanical injuries. In a normal individual, subcutaneous fat constitutes about 10% of body weight. According to Ackerman,5 the basic unit of the subcutaneous fat is the primary microlobule, which measures approximately 1 mm in diameter and is composed of a microscopic collection of adipocytes or lipocytes. Primary microlobules aggregate to form secondary lobules that measure approximately 1 cm in diameter and are surrounded by thin septa of connective tissue. The septa provide stability to the subcutaneous tissue by compartmentalization. The thickness of the subcutaneous fat varies from one part of the body to another, with a thinner subcutis in areas of lax skin, such as the eyelids and scrotum, and a thicker hypodermis in the hips and buttocks. There are also gender differences in the distribution of subcutaneous fat, and an increased thickness of the subcutis results in the rounded contours of the female torso, hips, pubis, and thighs. Underlying the morphologic heterogeneity of the subcutaneous fat is the demonstration that adipocytes from different sites of the same individual show differences in metabolic activity.6 The adipocytes derive from mesenchymal stem cells and represent a specialized component of the connective tissue capable of fat synthesis and fat storage. Considered as individual cells, the adipocytes are large, with a diameter up to 100 mm, and with hematoxylin-eosin stain appearing as empty cells with signet-ring morphology. This is because the lipid content dissolves in routinely processed specimens and the flat spindle nucleus is displaced at the periphery of the cell by a single, large intracytoplasmic vacuole, which contains fat. Frozen sections or other techniques must be used to demonstrate the adipocytes in their full monotonous splendor because of their cytoplasmic contents of essentially neutral lipids and triglycerides. Each adipocyte is separated from their neighbors by an inconspicuous matrix and they express S-100 protein and vimentin in immunohistochemical stains.7 The septa that divide the subcutaneous fat into lobules are thin and are composed of collagen
and reticulin fibers that are extensions of the dermis. This close relationship between dermal structures and subcutis may explain why some dermal inflammatory conditions may secondarily affect the septa of panniculus giving rise to septal panniculitis, such as necrobiosis lipoidica, deep morphea, subcutaneous granuloma annulare, rheumatoid nodule, and necrobiotic xanthogranuloma. These septa house the blood and lymphatic vessels and the nerves. Arteries and veins of the subcutis run along the septa. Each individual secondary lobule is supplied by a small muscular artery (250–500 mm diameter) branching from the septa to form arterioles (100–300 mm in diameter) that supply every individual primary microlobule. The arteriole branches to form capillaries into the microlobule, and a capillary network surrounds each individual adipocyte. Probably, adipocytes are the individual cells of the human body with a better vascular supply. Postcapillary venules meet in veins, which also run along the septa. In each microlobule, the arteriole occupies a central position, whereas the venule runs along the periphery.5 As a consequence, interference with the arterial supply results in diffuse changes within the lobule (mostly lobular panniculitis), whereas venous disorders are manifested by alterations in the septal and paraseptal areas (mostly septal panniculitis).8 This peculiar structure of the blood supply in subcutaneous fat explains why largevessel vasculitis involving the septal vessels is usually accompanied by little inflammation of the fat lobules, whereas when the vasculitis involves small blood vessels, there is extensive necrosis of the adipocytes with centrilobular infarct and dense inflammatory infiltrate within the lobule. In contrast with the dermal vascularization, the blood supply of each subcutaneous microlobule is terminal, implying there are no capillary connections between adjacent microlobules or between dermis and subcutaneous fat. The septa of the subcutaneous fat also contain a rich lymphatic plexus, which comes from the dermis and transverses the subcutis, first parallel to the surface of the skin and then vertically penetrating the deep fascia and draining into the regional lymph nodes. A crucial histopathologic point in the study of panniculitis with large-vessel vasculitis is to differentiate whether the involved vessel is artery or vein. A peculiarity of the veins in the subcutaneous fat of the lower limbs is that they often have an arterial appearance because they have a thick muscular layer.9 With hematoxylin-eosin stain, however, the venous nature of these vessels may be determined because the middle layer of the subcutaneous veins is composed of
Anatomy and Histology of Normal Subcutaneous Fat
Box 1 Classification of the panniculitides Mostly septal panniculitides With vasculitis Veins: superficial thrombophlebitis Arteries: cutaneous polyarteritis nodosa No vasculitis Lymphocytes and plasma cells mostly With granulomatous infiltrate in septa: necrobiosis lipoidica No granulomatous infiltrate in septa: deep morphea Histiocytes mostly: granulomatous infiltrate With mucin in center of palisaded granulomas: subcutaneous granuloma annulare With fibrin in center of palisaded granulomas: rheumatoid nodule With large areas of degenerated collagen, foamy histiocytes, and cholesterol clefts: Necrobiotic xanthogranuloma Without mucin, fibrin, or degeneration of collagen, but with radial granulomas in septa: Erythema nodosum Mostly lobular panniculitides With vasculitis Small vessels Venules: Erythema nodosum leprosum Lucio phenomenon Large vessels Arteries and veins: erythema induratum of Bazina
Neutrophils predominant Extensive fat necrosis with saponification of adipocytes: pancreatic panniculitis With neutrophils between collagen bundles of deep reticular dermis: a1-antitrypsin deficiency panniculitis With bacteria, fungi, or protozoa: infective panniculitis With foreign bodies: factitial panniculitis Histiocytes predominant (granulomatous) No crystals in adipocytes Subcutaneous sarcoidosis Traumatic panniculitis Lipomembranous fat necrosis Lipodystrophy and lipoatrophy With crystals in histiocytes or adipocytes Subcutaneous fat necrosis of the newborn Poststeroid panniculitis With cytophagic histiocytes: cytophagic histiocytic panniculitis Panniculitis-like subcutaneous lymphomasb With sclerosis of the septa: sclerosing postirradiation panniculitis a Sometimes, involvement of small blood vessels of the fat lobule may be prominent. b Although they are not authentic panniculitic processes but neoplastic proliferations of lymphocytes, they are included in the classification of the panniculitides because they may mimic panniculitis both clinically and histopathologically.
No vasculitis Few or no inflammatory cells Necrosis at the center of the lobule: sclerosing panniculitis With vascular calcification: calciphylaxis With needle-shaped crystals in adipocytes: sclera neonatorum Lymphocytes predominant With superficial and deep perivascular dermal infiltrate: cold panniculitis With lymphoid follicles, plasma cells, and nuclear dust of lymphocytes: lupus panniculitis
several muscular fascicles separated by tiny unstained elastic fibers, whereas arteries show a more compact muscular layer. In classic pathology, many authors continue to promote the misleading notion that arteries of the subcutaneous fat of the lower legs have a thicker muscular layer than veins. This is not necessarily true, however, because often veins show thicker muscular layer than arteries. In difficult cases, elastic tissue stain allows definite discrimination between artery and vein, because arteries show a wellformed, thick internal elastic lamina, whereas veins have a less evident internal elastic lamina and show tiny elastic fibers interspersed between muscular fascicles of the middle layer of the vessel wall.
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Fig. 1. Necrotic adipocytes. The nuclei are lacking and fat cells appear as round empty bags without inflammatory infiltrate among them. Hematoxylin-eosin stain, original magnification 200.
Fig. 3. Liquefactive fat necrosis. Loss of adipocytes, presence of granular wisps of amphophilic material. Hematoxylin-eosin stain, original magnification 200.
One of the main pitfalls for histopathologic interpretation of panniculitic biopsy specimens results from the fact that necrotic adipocytes exhibit a different appearance from other necrotic cells.10,11 In classic histopathology, nuclear abnormalities, namely, pyknosis, karyorrhesis, and kariolysis, are signs of cellular necrosis. In contrast, necrotic adipocytes, regardless of the injury resulting in cell death, may appear as either anucleated cells or with complete disintegration of the cellular structure.10 Often, the lack of nuclei is the only sign of necrosis of the adipocytes and the fat cells appear as round empty bags with no inflammatory infiltrate among them (Fig. 1). In only a few instances a concrete type of necrosis may orientate to a specific form of panniculitis. The most common type of
fat necrosis is the so-called ‘‘lipophagic necrosis,’’ which consists of the replacement of necrotic adipocytes by foamy macrophages laden with the lipid products released from dead adipocytes. These lipophages often exhibit a large, pale microvacuolated or granular cytoplasm (Fig. 2). Many panniculitides exhibit this pattern of necrosis at its late-stage. It is constantly observed in traumatic panniculitis and very frequently in lipodermatosclerosis, but may also be present in erythema nodosum and nodular vasculitis.11 Liquefactive fat necrosis is another type of necrosis of adipocytes that produces granular wisps of amphophilic detritus and the cellular structures of the adipocytes are no longer evident. This pattern of necrosis can be seen in a1-antitrypsin deficiency panniculitis and in pancreatic panniculitis (Fig. 3). Enzymatic fat necrosis is a special type of liquefactive fat necrosis characteristically
Fig. 2. Lipophagic necrosis. Necrotic adipocytes are replaced by foamy macrophages with a large, pale microvacuolated cytoplasm. Hematoxylin-eosin stain, original magnification 400.
Fig. 4. Enzymatic fat necrosis. Ghost adipocytes with granular basophilic cytoplasm caused by the saponification of lipid content. Hematoxylin-eosin stain, original magnification 400.
NECROSIS OF THE ADIPOCYTES
Anatomy and Histology of Normal Subcutaneous Fat
Fig. 5. Hyalinizing fat necrosis. Mummified anucleated adipocytes surrounded by glassy homogeneous material. Hematoxylin-eosin stain, original magnification 100.
observed in pancreatic panniculitis caused by saponification of the adipocyte lipid contents by pancreatic lipase, with secondary calcium salts deposition, resulting in ghost adipocytes, which show no nuclei and granular basophilic cytoplasm (Fig. 4). Hyalinizing fat necrosis results in mummified anucleated adipocytes and is surrounded by glassy homogeneous proteinaceous material that effaces their architecture (Fig. 5). This necrosis is characteristically observed in lupus panniculitis and in panniculitis associated with dermatomyositis, but it may also be seen in lipodermatosclerosis. Membranous fat necrosis is a late-stage necrosis of adipocytes that appears as a leathery eosinophilic or amphophilic rim of collapsed cellular organelles with a crenulated or arabesque appearance staining positively with periodic acidSchiff and Sudan III (Fig. 6). When membranous fat necrosis is extensive, fat microcysts devoid of cell structures and lined by hyaline-crenulated
Fig. 6. Membranous fat necrosis. Pseudocystic cavity with leathery eosinophilic rim. Hematoxylin-eosin stain, original magnification 400.
Fig. 7. Microcystic fat necrosis. Large fat pseudocyst devoid of cell structures and lined by a hyaline-crenulated membrane. Hematoxylin-eosin stain, original magnification 200.
membranes appear (Fig. 7). These latter forms of necrosis are extensive and almost constant in lipodermatosclerosis. A certain degree of membrano-cystic changes can be seen in a great number of panniculitis, however, especially in advanced stages. Ischemic fat necrosis is characterized by pallor of adipocytes caused by severe impairment of blood supply, mostly seen at the center of the involved lobules. In the first stages the changes are subtle, but in fully developed lesions adipocytes appear as empty ghost cells with preserved outlines of smaller size than normal adipocytes (Fig. 8). Later stages of ischemic necrosis are also characterized by lipophagic necrosis. It is frequently observed in erythema induratum of Bazin but can also be present in other panniculitis,
Fig. 8. Ischemic fat necrosis. Anucleated cells of smaller size than normal adipocytes with enlargement of the interstitium. Hematoxylin-eosin stain, original magnification 200.
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Segura & Requena REFERENCES
Fig. 9. Basophilic fat necrosis in an infectious panniculitis caused by gram-positive cocci. Note necrotic adipocytes intermingled with nuclear dust of neutrophils and basophilic granular material that represent aggregates of bacteria. Hematoxylin-eosin stain, original magnification 200.
such as calciphylaxis, infectious panniculitis, or cutaneous polyarteritis nodosa.11 Finally, basophilic fat necrosis results from necrosis of the adipocytes intermingled with disintegrated neutrophils and granular basophilic material, which represent aggregated bacteria (Fig. 9) and is mostly seen in infectious panniculitis. In this issue, a comprehensive clinicopathologic overview of the panniculitides is presented. Emphasis is put on the characteristic histopathologic features for specific diagnosis, and each article includes short comments about the treatment for each entity.
1. Patterson JW. Panniculitis: new findings in the third compartment. Arch Dermatol 1987;123:1615–8. 2. Requena L, Sa´nchez Yus E. Panniculitis. Part I. Mostly septal panniculitis. J Am Acad Dermatol 2001;45:163–83. 3. Requena L, Sa´nchez Yus E. Panniculitis. Part II. Mostly lobular panniculitis. J Am Acad Dermatol 2001;45:325–61. 4. Lundgren H, Bengtsson C, Blone E, et al. Adiposity and adipose tissue distribution in relation to incidence of diabetic women. Int J Obes 1989;13:413–8. 5. Ackerman AB. Panniculitis. In: Ackerman AB, editor. Histopathologic diagnosis of inflammatory skin diseases. Philadelphia: Lea & Febiger; 1978. p. 779–825. 6. Hirsch J, Goldrick B. Metabolism of human adipose tissue in vitro. In: Renold AE, Cahill GF Jr, editors. Handbook of physiology, Section V. Washington, DC: American Physiological Society; 1965. p. 455–70. 7. Kanitakis J. Immunohistochemistry of normal human skin. Eur J Dermatol 1998;8:539–47. 8. Reed RJ, Clark WH, Mihm MC. Disorders of the panniculus adiposus. Hum Pathol 1973;4:219–29. 9. Sa´nchez Yus E, Simo´n P, Sanz Vico D. Vena o arteria? Una cuestio´n decisiva en patologı´a hipode´rmica. PieI 1987;2:213–7. 10. White WL, Wieselthier JS, Hitchcock MG. Panniculitis: recent developments and observations. Semin Cutan Med Surg 1996;15:278–99. 11. Diaz Cascajo C, Borghi S, Weyers W. Panniculitis: definition of terms and diagnostic strategy. Am J Dermatopathol 2000;22:530–49.
of the inflammatory infiltrate cells change within the course of a few days, and often biopsies are taken from late-stage lesions because of inadequate clinicopathologic correlation and they show nonspecific findings. Some authorities believe that ‘‘the histologic septal-lobular dichotomy is sometimes diagnostically useful, but more often there is a mixed picture that adds to interpretative difficulties.’’1 Despite these pitfalls, the authors believe that with an adequate biopsy and performing serial sections through the specimen, dermatopathologists may classify the panniculitic process as a mostly septal or a mostly lobular panniculitis, and this classification system is very helpful for initial diagnostic purposes. This is just the first step in the diagnostic process, however, and it should be followed by the search of additional histopathologic findings that allow a more specific final diagnosis in the language of clinical dermatology. The second step in the histopathologic diagnosis deals with the assessment of whether vasculitis is or is not present, and when it is present the nature of the involved blood vessel should be determined. Finally, the third diagnostic step is the identification of the nature of the cells that compose the inflammatory infiltrate and the search for additional
a
Department of Dermatology, Hospital del Mar, IMAS, Passeig Marı´tim 25-29, 08003 Barcelona, Spain Department of Dermatology, Fundacio´n Jime´nez Dı´az, Universidad Auto´noma, Avda. Reyes Cato´licos 2, 28040, Madrid, Spain * Corresponding author. E-mail address: [email protected] (S. Segura). b
Dermatol Clin 26 (2008) 419–424 doi:10.1016/j.det.2008.05.011 0733-8635/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
derm.theclinics.com
The panniculitides comprise a heterogeneous group of inflammatory diseases involving the subcutaneous fat. These disorders have been classically considered diagnostically challenging, both for dermatologists and dermatopathologists, for several reasons. First, from a clinical point of view, dermatologists are used to evaluating different morphologic aspects of the altered skin to render a diagnosis, but subcutaneous tissue is not visible to examining eye. Instead, the lesions usually show a disappointing monotony, and entirely disparate diseases involving the subcutaneous fat appear with the same morphology, which consists of erythematous nodules, mostly located on the lower limbs. Second, the lesions are situated deep in subcutaneous tissue and large excision biopsies through subcutaneous fat must be performed for diagnosis to evaluate correctly the pattern of the inflammatory cell infiltrate and the involvement of blood vessels. Third, from a histopathologic point of view, the subcutaneous fat responds to a variety of insults in a limited number of forms, and pathologic differences between some of the conditions are sometimes subtle. Moreover, the panniculitides, like other inflammatory diseases of the skin, are dynamic processes in which both the composition and the distribution
420
Segura & Requena histopathologic features that allow a specific diagnosis. Box 1 provides a working classification of the panniculitides using this approach for diagnosis.2,3
ANATOMY AND HISTOLOGY OF THE SUBCUTANEOUS TISSUE Subcutaneous tissue is widely scattered throughout the body, forming a true organ as regards both structure and function.4 This tissue is crucial for thermal regulation, insulation, provision of energy, and protection from mechanical injuries. In a normal individual, subcutaneous fat constitutes about 10% of body weight. According to Ackerman,5 the basic unit of the subcutaneous fat is the primary microlobule, which measures approximately 1 mm in diameter and is composed of a microscopic collection of adipocytes or lipocytes. Primary microlobules aggregate to form secondary lobules that measure approximately 1 cm in diameter and are surrounded by thin septa of connective tissue. The septa provide stability to the subcutaneous tissue by compartmentalization. The thickness of the subcutaneous fat varies from one part of the body to another, with a thinner subcutis in areas of lax skin, such as the eyelids and scrotum, and a thicker hypodermis in the hips and buttocks. There are also gender differences in the distribution of subcutaneous fat, and an increased thickness of the subcutis results in the rounded contours of the female torso, hips, pubis, and thighs. Underlying the morphologic heterogeneity of the subcutaneous fat is the demonstration that adipocytes from different sites of the same individual show differences in metabolic activity.6 The adipocytes derive from mesenchymal stem cells and represent a specialized component of the connective tissue capable of fat synthesis and fat storage. Considered as individual cells, the adipocytes are large, with a diameter up to 100 mm, and with hematoxylin-eosin stain appearing as empty cells with signet-ring morphology. This is because the lipid content dissolves in routinely processed specimens and the flat spindle nucleus is displaced at the periphery of the cell by a single, large intracytoplasmic vacuole, which contains fat. Frozen sections or other techniques must be used to demonstrate the adipocytes in their full monotonous splendor because of their cytoplasmic contents of essentially neutral lipids and triglycerides. Each adipocyte is separated from their neighbors by an inconspicuous matrix and they express S-100 protein and vimentin in immunohistochemical stains.7 The septa that divide the subcutaneous fat into lobules are thin and are composed of collagen
and reticulin fibers that are extensions of the dermis. This close relationship between dermal structures and subcutis may explain why some dermal inflammatory conditions may secondarily affect the septa of panniculus giving rise to septal panniculitis, such as necrobiosis lipoidica, deep morphea, subcutaneous granuloma annulare, rheumatoid nodule, and necrobiotic xanthogranuloma. These septa house the blood and lymphatic vessels and the nerves. Arteries and veins of the subcutis run along the septa. Each individual secondary lobule is supplied by a small muscular artery (250–500 mm diameter) branching from the septa to form arterioles (100–300 mm in diameter) that supply every individual primary microlobule. The arteriole branches to form capillaries into the microlobule, and a capillary network surrounds each individual adipocyte. Probably, adipocytes are the individual cells of the human body with a better vascular supply. Postcapillary venules meet in veins, which also run along the septa. In each microlobule, the arteriole occupies a central position, whereas the venule runs along the periphery.5 As a consequence, interference with the arterial supply results in diffuse changes within the lobule (mostly lobular panniculitis), whereas venous disorders are manifested by alterations in the septal and paraseptal areas (mostly septal panniculitis).8 This peculiar structure of the blood supply in subcutaneous fat explains why largevessel vasculitis involving the septal vessels is usually accompanied by little inflammation of the fat lobules, whereas when the vasculitis involves small blood vessels, there is extensive necrosis of the adipocytes with centrilobular infarct and dense inflammatory infiltrate within the lobule. In contrast with the dermal vascularization, the blood supply of each subcutaneous microlobule is terminal, implying there are no capillary connections between adjacent microlobules or between dermis and subcutaneous fat. The septa of the subcutaneous fat also contain a rich lymphatic plexus, which comes from the dermis and transverses the subcutis, first parallel to the surface of the skin and then vertically penetrating the deep fascia and draining into the regional lymph nodes. A crucial histopathologic point in the study of panniculitis with large-vessel vasculitis is to differentiate whether the involved vessel is artery or vein. A peculiarity of the veins in the subcutaneous fat of the lower limbs is that they often have an arterial appearance because they have a thick muscular layer.9 With hematoxylin-eosin stain, however, the venous nature of these vessels may be determined because the middle layer of the subcutaneous veins is composed of
Anatomy and Histology of Normal Subcutaneous Fat
Box 1 Classification of the panniculitides Mostly septal panniculitides With vasculitis Veins: superficial thrombophlebitis Arteries: cutaneous polyarteritis nodosa No vasculitis Lymphocytes and plasma cells mostly With granulomatous infiltrate in septa: necrobiosis lipoidica No granulomatous infiltrate in septa: deep morphea Histiocytes mostly: granulomatous infiltrate With mucin in center of palisaded granulomas: subcutaneous granuloma annulare With fibrin in center of palisaded granulomas: rheumatoid nodule With large areas of degenerated collagen, foamy histiocytes, and cholesterol clefts: Necrobiotic xanthogranuloma Without mucin, fibrin, or degeneration of collagen, but with radial granulomas in septa: Erythema nodosum Mostly lobular panniculitides With vasculitis Small vessels Venules: Erythema nodosum leprosum Lucio phenomenon Large vessels Arteries and veins: erythema induratum of Bazina
Neutrophils predominant Extensive fat necrosis with saponification of adipocytes: pancreatic panniculitis With neutrophils between collagen bundles of deep reticular dermis: a1-antitrypsin deficiency panniculitis With bacteria, fungi, or protozoa: infective panniculitis With foreign bodies: factitial panniculitis Histiocytes predominant (granulomatous) No crystals in adipocytes Subcutaneous sarcoidosis Traumatic panniculitis Lipomembranous fat necrosis Lipodystrophy and lipoatrophy With crystals in histiocytes or adipocytes Subcutaneous fat necrosis of the newborn Poststeroid panniculitis With cytophagic histiocytes: cytophagic histiocytic panniculitis Panniculitis-like subcutaneous lymphomasb With sclerosis of the septa: sclerosing postirradiation panniculitis a Sometimes, involvement of small blood vessels of the fat lobule may be prominent. b Although they are not authentic panniculitic processes but neoplastic proliferations of lymphocytes, they are included in the classification of the panniculitides because they may mimic panniculitis both clinically and histopathologically.
No vasculitis Few or no inflammatory cells Necrosis at the center of the lobule: sclerosing panniculitis With vascular calcification: calciphylaxis With needle-shaped crystals in adipocytes: sclera neonatorum Lymphocytes predominant With superficial and deep perivascular dermal infiltrate: cold panniculitis With lymphoid follicles, plasma cells, and nuclear dust of lymphocytes: lupus panniculitis
several muscular fascicles separated by tiny unstained elastic fibers, whereas arteries show a more compact muscular layer. In classic pathology, many authors continue to promote the misleading notion that arteries of the subcutaneous fat of the lower legs have a thicker muscular layer than veins. This is not necessarily true, however, because often veins show thicker muscular layer than arteries. In difficult cases, elastic tissue stain allows definite discrimination between artery and vein, because arteries show a wellformed, thick internal elastic lamina, whereas veins have a less evident internal elastic lamina and show tiny elastic fibers interspersed between muscular fascicles of the middle layer of the vessel wall.
421
422
Segura & Requena
Fig. 1. Necrotic adipocytes. The nuclei are lacking and fat cells appear as round empty bags without inflammatory infiltrate among them. Hematoxylin-eosin stain, original magnification 200.
Fig. 3. Liquefactive fat necrosis. Loss of adipocytes, presence of granular wisps of amphophilic material. Hematoxylin-eosin stain, original magnification 200.
One of the main pitfalls for histopathologic interpretation of panniculitic biopsy specimens results from the fact that necrotic adipocytes exhibit a different appearance from other necrotic cells.10,11 In classic histopathology, nuclear abnormalities, namely, pyknosis, karyorrhesis, and kariolysis, are signs of cellular necrosis. In contrast, necrotic adipocytes, regardless of the injury resulting in cell death, may appear as either anucleated cells or with complete disintegration of the cellular structure.10 Often, the lack of nuclei is the only sign of necrosis of the adipocytes and the fat cells appear as round empty bags with no inflammatory infiltrate among them (Fig. 1). In only a few instances a concrete type of necrosis may orientate to a specific form of panniculitis. The most common type of
fat necrosis is the so-called ‘‘lipophagic necrosis,’’ which consists of the replacement of necrotic adipocytes by foamy macrophages laden with the lipid products released from dead adipocytes. These lipophages often exhibit a large, pale microvacuolated or granular cytoplasm (Fig. 2). Many panniculitides exhibit this pattern of necrosis at its late-stage. It is constantly observed in traumatic panniculitis and very frequently in lipodermatosclerosis, but may also be present in erythema nodosum and nodular vasculitis.11 Liquefactive fat necrosis is another type of necrosis of adipocytes that produces granular wisps of amphophilic detritus and the cellular structures of the adipocytes are no longer evident. This pattern of necrosis can be seen in a1-antitrypsin deficiency panniculitis and in pancreatic panniculitis (Fig. 3). Enzymatic fat necrosis is a special type of liquefactive fat necrosis characteristically
Fig. 2. Lipophagic necrosis. Necrotic adipocytes are replaced by foamy macrophages with a large, pale microvacuolated cytoplasm. Hematoxylin-eosin stain, original magnification 400.
Fig. 4. Enzymatic fat necrosis. Ghost adipocytes with granular basophilic cytoplasm caused by the saponification of lipid content. Hematoxylin-eosin stain, original magnification 400.
NECROSIS OF THE ADIPOCYTES
Anatomy and Histology of Normal Subcutaneous Fat
Fig. 5. Hyalinizing fat necrosis. Mummified anucleated adipocytes surrounded by glassy homogeneous material. Hematoxylin-eosin stain, original magnification 100.
observed in pancreatic panniculitis caused by saponification of the adipocyte lipid contents by pancreatic lipase, with secondary calcium salts deposition, resulting in ghost adipocytes, which show no nuclei and granular basophilic cytoplasm (Fig. 4). Hyalinizing fat necrosis results in mummified anucleated adipocytes and is surrounded by glassy homogeneous proteinaceous material that effaces their architecture (Fig. 5). This necrosis is characteristically observed in lupus panniculitis and in panniculitis associated with dermatomyositis, but it may also be seen in lipodermatosclerosis. Membranous fat necrosis is a late-stage necrosis of adipocytes that appears as a leathery eosinophilic or amphophilic rim of collapsed cellular organelles with a crenulated or arabesque appearance staining positively with periodic acidSchiff and Sudan III (Fig. 6). When membranous fat necrosis is extensive, fat microcysts devoid of cell structures and lined by hyaline-crenulated
Fig. 6. Membranous fat necrosis. Pseudocystic cavity with leathery eosinophilic rim. Hematoxylin-eosin stain, original magnification 400.
Fig. 7. Microcystic fat necrosis. Large fat pseudocyst devoid of cell structures and lined by a hyaline-crenulated membrane. Hematoxylin-eosin stain, original magnification 200.
membranes appear (Fig. 7). These latter forms of necrosis are extensive and almost constant in lipodermatosclerosis. A certain degree of membrano-cystic changes can be seen in a great number of panniculitis, however, especially in advanced stages. Ischemic fat necrosis is characterized by pallor of adipocytes caused by severe impairment of blood supply, mostly seen at the center of the involved lobules. In the first stages the changes are subtle, but in fully developed lesions adipocytes appear as empty ghost cells with preserved outlines of smaller size than normal adipocytes (Fig. 8). Later stages of ischemic necrosis are also characterized by lipophagic necrosis. It is frequently observed in erythema induratum of Bazin but can also be present in other panniculitis,
Fig. 8. Ischemic fat necrosis. Anucleated cells of smaller size than normal adipocytes with enlargement of the interstitium. Hematoxylin-eosin stain, original magnification 200.
423
424
Segura & Requena REFERENCES
Fig. 9. Basophilic fat necrosis in an infectious panniculitis caused by gram-positive cocci. Note necrotic adipocytes intermingled with nuclear dust of neutrophils and basophilic granular material that represent aggregates of bacteria. Hematoxylin-eosin stain, original magnification 200.
such as calciphylaxis, infectious panniculitis, or cutaneous polyarteritis nodosa.11 Finally, basophilic fat necrosis results from necrosis of the adipocytes intermingled with disintegrated neutrophils and granular basophilic material, which represent aggregated bacteria (Fig. 9) and is mostly seen in infectious panniculitis. In this issue, a comprehensive clinicopathologic overview of the panniculitides is presented. Emphasis is put on the characteristic histopathologic features for specific diagnosis, and each article includes short comments about the treatment for each entity.
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