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Seminars in Diagnostic Pathology 34 (2017) 261–272

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Seminars in Diagnostic Pathology


journal homepage: www.elsevier.com/locate/serndb

Panniculitis: A summary
Mark R. Wick n
Section of Dermatopathology,Dermatopathology, Division of Surgical Pathology & Cytopathology, University of Virginia Medical Center, Charlottesville, VA, USA

art ic l e i nf o a b s t r a c t

The diagnosis of panniculitis is felt to be a confusing topic by some pathologists. This summarical article
Keywords: presents inflammatory diseases of the subcutis in a systematic fashion, based on whether they are
Pannniculitis centered on fibrovascular septa or the adipose lobules, and whether morphologic vasculitis is present or
Vasculitis not. Septocentric, non-vasculitis disorders include erythema nodosum, panniculitis that follows the use
Erythema nodosum of “biological” therapeutic agents, lipodermatosclerosis, post-irradiation panniculitis, morphea profunda,
Lipodermatosclerosis and necrobiosis lipodica profunda. Polyarteritis nodosa and Behçet's disease are the conditions that are
Post-irradiation panniculitis based in the subcutaneous septa with vasculitis. Predominantly-lobular panniculitides with no vasculitis
Morphea profunda
include pancreatogenic panniculitis, the panniculitis of alpha-1-antitrypsin deficiency, panniculitis as-
Behçet disease
sociated with lupus erythematosus and dermatomyositis, subcutaneous Sweet syndrome, eosinophilic
Polyarteritis nodosa
Necrobiosis lipoidica panniculitis, factitial panniculitis, cold panniculitis, panniculitis following injections of corticosteroids,
Erythema induratum, pancreatogenic pan- lipomembranous (ischemic) panniculitis; sclerema neonatorum and subcutaneous fat necrosis of the
niculitis newborn, and Rosai-Dorfman disease of the subcutis. Erythema induratum and infectious panniculitis
Alpha-1-antitrypsin deficiency are vasculitic and lobulocentric conditions. This article reviews the histological features of these diseases.
Lupus erythematosus & 2017 Elsevier Inc. All rights reserved.
Dermatomyositis
Sweet syndrome
Infectious panniculitis
Eosinophilic panniculitis
Factitial panniculitis
Cold panniculitis
Sclerema neonatorum
Subcutaneous fat necrosis of the newborn

The diagnosis of panniculitis is regarded as a bewildering subject Primarily-septal panniculitides


by some pathologists. Potentially-shared histological patterns are
common to several clinical disorders in that category of diseases, Principally-septal panniculitides without vasculitis
and some individual panniculitides also are capable of assuming
more than one microscopic appearance. This fact relates to the Erythema nodosum
reality that most inflammatory diseases of the panniculus begin as Erythema nodosum (EN) is the most commonly-encountered
neutrophilic infiltrates and may then “mature” into conditions with form of panniculitis. It is mainly seen in women during early
adulthood, manifesting with several nodular, reddish, minimally-
dissimilar, largely-mononuclear histologic components 1,2.
tender lesions that usually involve the anterior surfaces of the legs.
As outlined by Prieto & Ivan, inflammatory diseases of the fat are
Less often, other skin areas may be involved as well 4–9. Malaise,
primarily categorized by their microanatomical features, as septal—
low-grade fever, and leukocytosis may be present. The duration of
centered on the interlobular fibrovascular septa in the subcutis—or
EN varies from several weeks to several years, but the disorder is
lobular, involving the adipose lobules themselves (Tables 1 and 2). In
ultimately self-limited 4. It is potentially associated with under-
turn, that distribution relates to the sizes of the blood vessels on
lying infections– which may be bacterial, viral, fungal, or chla-
which the inflammation is focused. Septal disorders target large- and mydial– or with sarcoidosis and hematolymphoid diseases 10.
medium-sized vascular structures, whereas lobular lesions principally The microscopic image of EN is that of septal edema or fibrosis,
involve small vessels 3. They can be further subclassified using clinical and a mixed cellular infiltrate that potentially includes erythrocytes,
data and more detailed histological information (Figs. 1 and 2). neutrophils and eosinophils (in early lesions), lymphocytes, and
histiocytes (Fig. 3). Non-necrotizing septal microgranulomas are ty-
n
Coorrespondence address: University of Virginia Hospital, Room 3020, 1215 Lee
pical of fully-evolved lesions, including “Miescher” granulomas that
Street, Charlottesville, VA 22908-0214, USA. are centered on small blood vessels or slit-like virtual spaces 7. His-
E-mail address: mrwick1@usa.net tological findings that tend to militate against a diagnosis of EN

http://dx.doi.org/10.1053/j.semdp.2016.12.004
0740-2570/& 2017 Elsevier Inc. All rights reserved.
262 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 261–272

Table 1 the lesions resemble those of deep morphea or systemic sclerosis,


Predominantly-septal panniculitides. being depressed, discolored, and “hide-bound” areas in the skin.
 Histologically, one sees sclerotic thickening of the subcuticular fi-
Erythema nodosum
 Panniculitis following use of “biological” therapeutic agents brous septa, with a variable lymphoplasmacytic infiltrate. Lipo-
 Lipodermatosclerosis (sclerosing panniculitis) phagic granulomas also may be present in the fat lobules. The
 Post-irradiation panniculitis overlying corium contains sclerotic blood vessels with intimal fi-
 Morphea profunda
broplasia, and atypical polyploid dermal fibroblasts with pleo-
 Behcet's disease
 Polyarteritis nodosa morphic, hyperchromatic nuclei 12.
 Necrobiosis lipoidica Morphea profunda (subcutaneous morphea) has closely-similar
clinical and histologic appearances 13,14 (Fig. 4). It is not possible to
separate that condition definitively from post-irradiation panni-
culitis, even in patients with a history of that therapeutic
intervention.
Table 2
Predominantly-lobular panniculitides.
Subcuticular necrobiosis lipoidica
 Erythema induratum (Bazin disease; nodular vasculitis)n Necrobiosis lipoidica (NL) has been discussed separately in
 Pancreatic panniculitis another article in this issue of Seminars. In some examples of that
 Alpha 1-antitrypsin deficiency panniculitis
 disorder, it extends beyond the deep dermis into the subcutis,
Panniculitis in lupus erythematosus & dermatomyositis
 “Atypical lymphocytic lobular panniculitis” where it principally affects the septa with lesser lobular involve-
 Subcutaneous Sweet syndrome ment. Necrobiotic granulomas, lymphohistiocytic infiltrates, and
 Infectious panniculitides* fibrosis typify the lesions histologically 15–17 (Fig. 5). The epicenter
 Eosinophilic panniculitis (including Churg-Strauss syndrome*)
of NL is in the mid-dermis, and the entirety of the corium is
 Factitial panniculitis
 Cold panniculitis characteristically involved by granulomatous inflammation.
 Sclerema neonatorum
 Subcutaneous fat necrosis of the newborn Lipodermatosclerosis (sclerosing panniculitis)
 Panniculitis following steroid injections Lipodermatosclerosis (LDS) is synonymous with “sclerosing
 Lipomembranous (ischemic) panniculitis
 Rosai-Dorfman disease
panniculitis.” It is seen in the lower legs, principally in obese pa-
tients who have venous insufficiency. The skin is grossly indurated
n
Vasculitis is present in these disorders. and shiny, with increased pigmentation or erythema. The legs
often macroscopically resemble inverted champagne bottles or
include morphological vasculitis, necrosis, and an overriding dom- upside-down bowling pins, because the circumference of the
inance of epithelioid granulomas 3. distal lower extremities is diminished 18–21.
Lesions that are virtually identical to those of EN can be seen Histologically, LDS demonstrates septal fibrosis and mild lym-
after the administration of “biological” therapeutic agents 11. Those phoplasmacytic inflammation, with sclerosis of blood vessels.
include such drugs as adalimumab, imatinib, BRAF inhibitors, and Atrophy of fat lobules may be seen, and the dermis often exhibits
immune checkpoint modulators. the morphological changes of vascular stasis 18,19,21.

Post-irradiation panniculitis & morphea profunda Principally-septal panniculitides with vasculitis


Panniculitis may follow the administration of radiotherapy,
within the radiation field, months or years thereafter. Clinically, Only two forms of panniculitis feature septocentricity together

Fig. 1. Algorithm for the diagnosis of predominantly-septal panniculitides.


M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 261–272 263

Fig. 2. Algorithm for the diagnosis of predominantly-lobular panniculitides.

Fig. 3. Erythema nodosum produces nodular reddish subcutaneous nodules, usually on the anterior lower legs (top left). The septal distribution of inflammation in this
disorder is shown in the top right & bottom left panels. It principally comprises lymphocytes and histiocytes in well-developed lesions, sometimes with multinucleated giant
cells (bottom right panel).
264 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 261–272

Fig. 4. Morphea profunda of the thigh is seen in the upper left panel, manifested by discolored and depressed areas in the skin. Microscopically, it exhibits dense fibrosis of
the subcutaneous septa, together with lymphohistiocytic infiltrates (right panels).

Fig. 5. Necrobiosis lipoidica presents with indurated and red-brown plaques, usually on the shins (left panel). When it involves the hypodermis, subcutaneous septa are
fibrotic and they also show lymphohistiocytic infiltrates with necrobiosis (right panels).

with vasculitis. They are polyarteritis nodosa (PAN) and involve- joints and lungs. Mucocutaneous ulcers in BD are aphthous in nature,
ment of the subcutis by Behçet s disease (BD). Clinically, both of with common localization in the oral mucosa and genital skin 17,22.
those diseases present with cutaneous ulcers in adults, with or Histologically, the most consistent difference between PAN and
without tender nodular reddish subcutaneous nodules. PAN is often BD is the nature of the inflammatory cells that effect the vasculitic
further characterized by livedo reticularis, myalgias, neuropathy, lesions. PAN is typified by transmural neutrophilic infiltrates of large,
hypertension, renal insufficiency, infection by the hepatitis B virus, medium-sized, and small arteries, together with fibrinoid change of
and the formation of aneurysms in visceral arteries. The lungs are the vascular media (Fig. 6). In contrast, BD usually features a lym-
unaffected. On the other hand, BD is associated with mucocutaneous, phocytic vasculitis that principally affects small arteries and veins
ocular, cardiovascular, renal, gastrointestinal, pulmonary, urologic, without fibrin deposition (Fig. 7). Uncommonly, a leukocytoclastic
and central nervous system lesions, as well as involvement of the venulitis may be present in that condition instead 2,17,23.
M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 261–272 265

Fig. 6. Polyarteritis nodosa (PAN) is shown here, with ulcers and confluent zones of cutaneous induration on the lower legs (left panel). Microscopically, PAN affects large
blood vessels in the subcutaneous septa, which show neutrophilic vasculitis and fibrinoid change (right panels).

Fig. 7. Behcet's panniculitis (BP) is shown at the top left, with multiple reddish nodules in the subcutis of the lower legs. Microscopically, BP is centered on the subcutaneous
septa (top right), and it shows the presence of lymphocytic vasculitis (bottom panels).

Primarily-lobular panniculitides form of “tuberculid” (an immune reaction in the skin to infection
with Mycobacterium tuberculosis) by many observers, together
Principally-lobular panniculitis with vasculitis with lichen scrofulosorum and papulonecrotic tuberculid 27. An
alternate view is that EI represents a generic cutaneous vasculitis
Erythema induratum and infections account for the principally- pattern with several potential etiologies, only one of which is tu-
lobular forms of panniculitis that include morphologic vasculitis. berculous in nature; infection with the hepatitis C virus and in-
flammatory bowel disease have also been implicated in some
Erythema Induratum (nodular vasculitis; bazin disease) instances 18,23,24,28.
Erythema induratum (EI) mainly affects the subcutis of the EI presents with multiple reddish, tender plaques and nodules
lower legs in middle-aged or elderly women; men are more un- that often ulcerate, in patients who are otherwise well. This con-
commonly affected 18,23–26. This disease is still considered to be a dition follows a cyclic course, with spontaneous involution and
266 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 261–272

Fig. 8. Erythema induratum (nodular vasculitis; Bazin disease) typically causes ulcerating nodular lesions in the hypodermis of the lower legs, usually in middle-aged or
elderly women (top left panel). It manifests histologically with a lobulocentric lymphohistiocytic infiltrate (top right), with vasculitis (bottom left) and potentially-necro-
tizing granulomatous inflammation (bottom right).

then recurrence of the lesions over months to years. Appropriate possible pathogens can be identified by formal culturing of the
treatment of associated infections—if any can be identified—is lesions or microscopic examination of biopsy specimens. They
usually undertaken, and local injections of corticosteroids into the include several bacteria (Streptococcus; Staphyloccus; Pseudomo-
lesions have been used as well 24,25. nas; typical and atypical Mycobacteria; Actinomyces; Hemophilus;
A histopathologic study of several cases of EI by Schneider & Nocardia; Klebsiella; Acinetobacter; and Borrelia); fungi (Sporothrix;
Jordaan 29 showed the presence of diffuse lobular panniculitis, Fonsecaea; Phialophora; Rhinocladiella; Cladophialophora; Madur-
with lesser septal involvement. A primary neutrophilic or lym- ella; Acremonium; Curvularia; Pseudallescheria; Blastomyces; Histo-
phocytic vasculitis of large or small subcutaneous vessels was plasma; Cryptococcus; Penicillium; Aspergillus; Fusarium; and Can-
present, together with varying combinations of acute and chronic dida); parasitic organisms (Leishmania; Toxoplasma; Spirometra;
inflammation in the fat lobules with coagulative and caseating- and Gnathostoma); and cytomegalovirus 30,33,34.
type necrosis and granulomatous inflammation (Fig. 8). Ill-formed Histologically, IP manifests with mixed inflammatory infiltrates
granulomas were the most common, but palisading and lipophagic which are centered in the subcutaneous lobules. Neutrophils
granulomatous lesions also were observed. Immunostaining de- usually predominate, but they are often admixed with granulomas
monstrated the presence of antigen-presenting cells, macro- and lymphocytes. Morphological vasculitis can be seen that affects
phages, and T-lymphocytes. In other analyses, studies of EI lesions large and small vessels alike, sometimes with fibrinoid changes.
with the polymerase chain reaction have demonstrated myco- Obviously, histochemical assessment is necessary in all potential
bacterial antigens in a significant proportion of cases 23. cases of IP, including tissue Gram, periodic acid-Schiff, Gomori
methenamine-silver, acid-fast, and Giemsa stains 30,31.
Infectious panniculitides
The topic of infectious panniculitis (IP) has been reviewed by
Morrison et al. It can be seen as a primary process in the subcutis Principally-lobular panniculitis without vasculitis
after direct inoculation of microbes by trauma or direct extension
from a cutaneous or deep soft tissue infection. Alternatively, sec- Even though EN—a principally-septal process—is the most com-
ondary IP results from the hematogenous spread of a systemic monly-encountered form of panniculitis overall, the list of lobular
infection. Several potential anatomical sites for IP have been de- and non-vasculitic panniculitides is numerically more extensive than
scribed, but it usually affects the extremities and truncal skin. that of the septocentric conditions. It encompasses subcutaneous
Many patients with IP are immunocompromised or they are in- inflammation associated with pancreatic diseases; α 1-antitrypsin
travenous drug abusers 30,31. deficiency; lupus erythematosus & dermatomyositis; atypical lym-
Clinically, the lesions of IP may resemble those of EN, or they phoid infiltrates; Sweet syndrome; eosinophilic infiltrates; factitial
may be larger, more erythematous, and potentially-ulcerated. Fe- injuries; exposure to the cold; degenerative conditions of infancy;
ver and general malaise are common coincident findings 32. Many prior steroid injections; ischemia; and Rosai-Dorfman disease.
M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 261–272 267

Pancreatogenic panniculitis both) as well. The skin lesions remit after intravenous infusions of
Rarely, patients with pancreatitis (acute or chronic), pancreatic exogenous α 1-antitrypsin 45.
pseudocysts, or pancreatic neoplasms may develop a singular form Histologically, AATD panniculitis exhibits neutrophilic in-
of lobular panniculitis 35–38. Current thinking holds that elevated filtrates in the deep corium and subcuticular adipose lobules, with
plasma levels of lipase and amylase cause these lesions by enzy- zones of fat necrosis (Fig. 10). Septal inflammation is often present
matic alteration of subcuticular adipose tissue. Dhawan et al. as well 46. Geller & Su 47 noted that neutrophils are also present
showed that intracellular immunohistochemical labeling for pan- between collagen bundles in the reticular dermis in this condition,
creatic lipase was present in this disorder 39. with incipient necrobiosis.
Pancreatogenic panniculitis (PP) typically affects the lower legs
of adults, where several variably-tender reddish nodules appear. Lymphocytic panniculitis in connective tissue disorders & lymphoid
This condition may be seen several weeks before or after the dyscrasia
pancreatic abnormality is recognized. Acinar-cell carcinoma is the Patients with systemic or discoid lupus erythematosus (LE) or
specific tumor type that most often is associated with neoplastic dermatomyositis (DM) develop panniculitis (lupus profundus) in a
PP 38. If the underlying glandular disease remits or is extirpated minority of cases, and it may rarely be the seminal manifestation
surgically, the panniculitis usually regresses but may leave residual of those disorders 48–54. The more common clinical and histolo-
foci of organized fat necrosis in the subcutis 35. gical findings in those conditions have been reviewed in another
Histopathologically, PP shows moderate lobular neutrophilia, paper in this issue.
with lesser numbers of lymphocytes and necrosis of adipocytes. The microscopic features of panniculitis in patients with LE or
The damaged fat cells contain finely-granular basophilic cyto- DM are comparable. They include diffuse lobular infiltrates of
plasmic material, representing calcium “milk” 35,36 (Fig. 9). Overt mature lymphocytes with no nuclear atypicality, associated with
foci of dystrophic calcification also are common, as are “ghost-like” multifocal hyalinization of the subcuticular fat 51,52 (Fig. 11).
outlines of necrotic fat cells. Another consideration has been described by Magro et al., in
reference to a disorder termed “atypical lobular lymphocytic
Panniculitis in α 1-antitrypsin deficiency panniculitis” (ALLP) 55. The latter condition resembles lupus
Panniculitis in patients with alpha-1-antitrypsin deficiency profundus histologically, but it shows clonality in genotypic
(AATD) is rare, with an estimated prevalence of 0.1% in individuals studies and presumably represents a form of quasi-neoplastic
who have a marked diminution of functional enzymatic activity lymphoproliferation (“lymphoid dyscrasia”) 56. Practically speak-
(typically with the PiZZ genotype) 40–45. Clinically, this disorder ing, there would appear to be no compelling reason to look for
presents with tender and ulcerating reddish subcutaneous no- T-cell receptor gene rearrangements in all cases of lymphocytic
dules; panniculitis may be the only sign of AATD, or it can be ac- panniculitis, because the clinical evolution of ALLP has typically
companied by panacinar emphysema or hepatic dysfunction (or been self-limiting rather than progressive 55,56. As outlined by

Fig. 9. The panniculitis of pancreatic disease presents with tender red-brown plaques and nodules (left panel). Histologically, one sees fat necrosis with “ghost” adipocytes
and calcification (right panels).
268 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 261–272

Fig. 10. Alpha-1-antitrypsin deficiency-related panniculitis causes reddish brown nodules in the subcutis that may ulcerate (left). Microscopically, it is represented by a
predominantly-lobular neutrophilic infiltrate with fat necrosis (right).

Shiau & colleagues, such studies are most appropriate when the cold panniculitis closely parallel those of LE/DM panniculitis, and
morphological features of a lymphocyte-predominant pannicu- therefore the clinical history is paramount in separating those disorders
litis suggest the likely presence of subcutaneous panniculitis-like from one another. In some cases of cold panniculitis, chronic in-
T-cell lymphoma or cutaneous γ- δ-cell lymphoma, which are flammation is particularly dense at the dermal-subcuticular interface 60.
also clonal proliferations but which feature the presence of vas-
culitis-like foci 57–59. Subcutaneous Sweet Syndrome
Sweet syndrome (acute aseptic neutrophilic dermatosis) has
Cold-induced panniculitis also been discussed elsewhere in this installment of Seminars. The
A form of panniculitis may be seen as an idiosyncratic response to dense dermal infiltrate of polymorphonuclear leukocytes which
cold exposure. It is most often encountered in children, or in adults characterizes that disease may extend into the subcutaneous lo-
who spend prolonged periods of time in the cold, affecting skin areas bules (and septa) as well, representing a specific form of neu-
that are exposed to the environment 60–62. The histological features of trophilic panniculitis. Uncommonly, small-vessel vasculitis in the

Fig. 11. Lupus erythematosus panniculitis (lupus profundus) presents with reddish nodules and depressed sclerotic plaques (left). The histologic image of that disease
features lobular lymphocytic infiltration with hyalinization of the adipose tissue (right).
M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 261–272 269

Fig. 12. Eosinophilic panniculitis is no different clinically from other forms of panniculitis (left), and it has several potential etiologies. This condition is represented by diffuse
lobular infiltration of the subcutis by eosinophils (right).

Fig. 13. Both subcutaneous fat necrosis of the newborn, shown here (left) and sclerema neonatorum are seen in infants. Both disorders feature the presence of crystal-like
inclusions in the subcutis microscopically (right), but they have dissimilar clinical evolutions.

63
subcutis may be present in this condition as well . disease 64–67. Hence, “eosinophilic panniculitis” is a descriptive
term rather than a specific entity.
Eosinophilic Lobular Panniculitis
Diffuse lobulocentric infiltrates of eosinophils in the superficial Factitial panniculitis
adipose tissue (Fig. 12) can be associated with a spectrum of Individuals with variants of the Munchhausen syndrome or
etiologies. They potentially include drug eruptions; reactions to other psychological disturbances may surreptitiously inject foreign
arthropod bites; a manifestation of parasitosis (e.g., sparganosis; materials (various chemicals; food; plant materials; feces; urine)
gnathostomiasis); Churg-Strauss disease; Shulman syndrome; into the subcutis for secondary emotional gain 68–70. The resulting
Kikuchi disease, hypereosinophilic syndrome, and Kimura lesions, known as factitial panniculitis, can be challenging to
270 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 261–272

Fig. 14. Lipomembranous panniculitis (membranous lipodystrophy; membranocystic fat necrosis) usually affects the lower legs (left). Histologically, it causes microcystic
change in the subcutis (top right), and “feathery” membranous alteration in adipocytes (bottom right).

Fig. 15. The macroscopic appearance of Rosai-Dorfman disease in the subcutis is shown in the left panel, represented by several nodules. Histologically, one sees either
lobular or lobular & septal lymphohistiocytic infiltrates (top right). Constituent histiocytes demonstrate lymphemperipolesis (bottom right).

recognize histopathologically because they present a diverse collections of amorphous amphophilic material may be present in
group of microscopic appearances. Usually, lobular inflammation the subcutaneous fat as well 71. Once again, clinical information is
is dominant, often including multinucleated foreign body-type vital to recognizing this condition.
giant cells, and polarizable material may be present 68.
Panniculitides of infancy—subcutaneous fat necrosis & sclerema
Panniculitis following exogenous steroid injection neonatorum
The chemical “carriers” of injectable corticosteroid preparations Two forms of panniculitis are histologically-singular, because they
may likewise induce a form of panniculitis that shows a micro- feature the presence of crystal-like inclusions within a mixed in-
scopic overlap with the factitial type. Sometimes, microscopic flammatory infiltrate in the subcutis, potentially also with multinucleated
M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 261–272 271

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