Chapter 70

Panniculitis
Iris K. Aronson, Patricia M. Fishman, &
Sophie M. Worobec

ADIPOSE TISSUE AND IMMUNITY

In the past 20 years, research into obesity has led
to a great deal of information about the function of
adipocytes and AT, and to the understanding that
adipocytes are central not only to energy homeostasis but also as cellular components of the innate
immune system and mediators of inflammation. AT
is an immunological active organ system that lies at
the crossroads of multiple important physiological
functions, including energy expenditures, appetite, insulin sensitivity, endocrine and reproductive
systems, bone metabolism, inflammation, and
immunity.5
Millions of invertebrate species rely solely on the
innate immune system as defense against infections.6 A hallmark of insect antimicrobial defense
is the organ called the fat body, which has receptors for bacterial and fungal cell wall molecules
known as Toll receptors. These receptors activate
the nuclear factor B (NF-B) signaling cascade,
inducing secretion of antimicrobial peptides and
other defensive molecules.7 The insect fat body is
analogous to the mammalian liver and in addition
to the immune functions, also manages the animals
liver functions and lipid storage.8 Subsequently, in
the evolution of vertebrates, these functions were
divided up between the liver and the AT, with the
latter retaining some functions of the innate immune system.8
As a cell of the innate immune system, the adipocyte is equipped to protect the organism from
pathogenic microbes by recognition of pathogen
associated molecular patterns (PAMPs) via receptors called pattern recognition receptors (PRRs).9
There are three types of PRRs: (1) transmembrane,
(2) cytosolic, and (3) secreted.911 Transmembrane
PRRs include Toll-like receptors (TLRs) and C-type
lectins.11 TLRs are expressed either on the plasma
membrane where they detect cell surface microbial patterns such as lipopolysaccharides (LPS) of
Gram-negative bacteria, or in endosomal/lysosomal
organelles, where they recognize mainly microbial

nucleic acids such as dsRNA (TLR3), ssRNA (TLR7),

and dsDNA (TLR9).11 Expression of TLRs is cell-type
specific, thereby allocating recognition responsibilities to different types of cells.11
C-type lectins dectin-1 and -2 recognize -glucans
and mannan of fungal cell walls.11 Cytosolic or
internal PRRs consist of nucleotide-binding domain
and leucine-rich repeat containing receptors (NLRs)
which include the large NOD receptor family, and
retinoic acid-inducible gene I (RIG-1)-like receptors
(RLRs), and recognize PAMPs in the internal compartment should the microbe evade extracellular
surveillance.11,12 Secreted PRRs include collectins,
ficollins, and pentraxins which bind to the surface
of microbes, activate the complement system, and
opsonize microbes for phagocytosis.11
Once activated, the PRRs activate proinflammatory signaling pathways, especially activation of transcriptions factors NF-B, interferon regulatory factor
3 (IRF3), or nuclear factor of activated T cells (NFAT),
that promote expression of genes involved in the
immune response mediated via multiple molecules
including cytokines, chemokines, antimicrobial
peptides, complement, adhesion molecules, and
cell membrane costimulatory molecules.11,13 TLRs
trigger activation of adaptive immunity responses
that include antibody responses, TH1, TH17 CD4+ T
cells, CD8+ T cells responses, and TH2 (via TLR4) and
IgE response.11 Cytosolic PRRs including RLRs and
some NLRs may also activate adaptive immunity.11
Adipocytes are the most abundant cells in white
AT (WAT), but other cell types are included in the
stromovascular fraction, including fibroblasts,
vascular endothelial cells, and inflammatory cells,
especially macrophages which makes up 10% of
that fraction but increase significantly in obesity.5
These macrophages along with other stromovascular cells contribute to the production and secretion
of humoral cytokines, especially the inflammatory
cytokines.5,14 The macrophages are bone-marrowderived from circulating monocytes infiltrating WAT,
and incubation with adipocyte-conditioned media
leads to increase in intercellular adhesion molecule
I (ICAM-1) and plateletendothelial cell adhesion
molecule 1 (P/E CAM-1) in endothelial cells, leading
to increased transmigration of blood monocytes to
AT.15,16 The same effect is seen with high-dose leptin
and monocyte chemotactic protein 1 (MCP-1).5
Macrophage-derived TNF induces adipocyte lipolysis, which leads to release of free fatty acids from

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Chapter 70:

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the adipocyte, which induces direct TLR4 signaling

and NF-B activation in macrophages.10 This paracrine loop involving inflammatory cytokines and
free fatty acids establishes a vicious cycle between
adipocytes and macrophages that propagates inflammation.17 Glucocorticoids and thiazolidinendiones have been shown to interfere with adipocyte
mediated macrophage chemotaxis and recruitment.18 Corticosteroids have been shown to reduce
the proinflammatory status of mature adipocytes
by inhibiting basal release of MCP-1 and resistin.19
AT also contains lymphocytes that contribute to
AT inflammation.20 The AT T cells differ from those of
other tissues and vary between different AT sites.20
The lymphocytes in epididymal AT are similar to
those of the liver with predominant expression of
ancestral innate immune system phenotype [natural killer (NK), T] in up to 65%, whereas the adaptive phenotype (, T and B cells) predominates in
blood, lymph nodes, and inguinal fat pads.20 Obesity causes site-specific changes in the proportions
of these phenotypes.20 It has recently been shown
that CD8+ T cells precede the accumulation of macrophages in AT, and in vitro coculture experiments
have shown a vicious cycle of interaction between
CD8+ T cells, macrophages, and AT, suggesting that
AT activates CD8+ T cells, which in turn promote the
recruitment and activation of macrophages.21
The interaction between adipocytes and lymphocytes was further explored when the inflammatory
receptor CD40 was shown to be expressed on
human adipocytes and to contribute to intercellular
cross talk between adipocyte and lymphocyte.22
Lymphocyte adipocyte coculture showed upregulation of proinflammatory adipocytokines, including
IL-6, MCP-1, and PAI-1, but downregulation of leptin
and adiponectin.22 T lymphocytes were shown to
regulate adipocytokine production, both through
release of soluble factors and heterotypic contact
with adipocytes involving the CD40/CD40 ligand (L)
pathway.22
Adipocytes also interact with blood vessels, and
cross talk between perivascular AT and blood vessels has been demonstrated.23 Cross talk between
AT and blood vessels is bidirectional, and dysfunction in either tissue influences the other.23 Perivascular AT secretes high levels of proinflammatory
cytokines such as IL-6, IL-8, and MCP-1 compared to
anti-inflammatory adiponectin, when compared to
other AT depots.24

NODULAR LESIONS OF THE LEGS

Erythema Induratum and
Nodular Vasculitis
ETIOLOGY AND PATHOGENESIS.
In the past, although EI was frequently associated with MTB, the etiology was still controversial
since organisms were not always identified in the
biopsies and tissue cultures of EI lesions. However,
with the advent of polymerase chain reaction (PCR)
techniques, multiple culture negative cases were
shown to contain MTB DNA in involved tissue.5658
Extracutaneous MTB is found in a significant
numbers of EI patients, and may be present in lung,
lymph nodes, kidney, or bowel.52 However, other infections or disorders have also been associated with
EI/NV; these include hepatitis B, hepatitis C (Red
finger syndrome and panniculitis), Crohns disease,
ulcerative colitis, leukemia, rheumatoid arthritis, hypothyroidism, and Nocardia infection.52,5962 Medications, for example, propylthiouracil, have also been
associated with EI/NV.63 In known endemic areas,
fungal infections should be sought as possible
etiological factors by stains, cultures, serology, and
PCR, if strongly suspected.
EI has been considered to be a hypersensitivity
disorder mediated by immune complexes or cellmediated hypersensitivity, as manifested by the
presence of highly positive tuberculin skin tests, T
lymphocyte hyperresponsiveness, and highly positive interferon- release assay tests to MBT.6466
The presence of MTB DNA in AT in the absence of
positive bacterial cultures has pointed to AT as location for persistence of latent infections. In situ and
conventional PCR techniques have shown that MTB
DNA can be detected in AT s of various anatomic
sites in patients who died from nontuberculosis etiologies and in perinodal AT of some patients who
died with MTB.67 In vitro studies show that MTB can
bind to scavenger receptors, enter adipocytes and,
via the nearly 20 lipases of MBT, can appropriate the
host lipids, accumulate intracytoplasmic lipid inclusions, and survive in a nonreplicating state that is
insensitive to the major antimycobacterial medication isoniazid.67 However, rifampin and ethambutol
can reduce MTB bacterial load in adipocytes by
80%90%.67 Other organisms that can infect adipocytes and serve as a reservoir of recurrent reactivation include cytomegalovirus (CMV), Chlamydia

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Chapter 70: Panniculitis 61

pneumoniae, adenovirus, influenza virus, respiratory syncytial virus (RSV), Rickettsia prowazekii, and
Trypanosoma cruzi.6871
Adipocytes are cells of the innate immune system.
Infection of adipocytes leads to activation of multiple signaling pathways, generating inflammatory
responses to each threat with various cytokines
and adipokines. These cytokines and adipokines
bring other innate immune cells (macrophages,
neutrophils, mast cells, NK cells) as well as adaptive
immune cells (sensitized T cells) to the infection site
that may help in containing infection. Why and how
certain infections persist in spite of the inflammatory and immune response may vary with the organism involved as well as the host immune system.
The location of the majority of EI/NV lesions in AT of
the legs may be related to venous or lymphatic vessel insufficiency, or to different functional capacities
of adipocytes in different locations.
PATHOLOGY.
Histopathological findings correlate with lesion
duration, but the common denominator is a mostly
lobular or mixed septal and lobular panniculitis (Fig.
70-6A). In early lesions, fat lobules contain discrete
aggregates of inflammatory cells, with neutrophils
predominating. Adipocyte necrosis is present to
varying degree, leading to accumulations of foamy
histiocytes. In established lesions of EI/NV, collections of epithelioid histiocytes, mutinucleated giant
cells, and lymphocytes produce a granulomatous
appearance. Intense vascular damage, when present, is accompanied by extensive areas of caseous
necrosis53,54 (Fig. 70-6B), eventuating in tuberculoid
granuloma formation. The caseous necrosis may
involve the overlying dermis to such an extent that
ulceration occurs.53
In a recent retrospective analysis by Segura et
al52 of 101 biopsies in 86 patients with the clinicopathologic diagnosis of EI, vasculitis of some type
was present in 90% of cases. The vessels involved
were lobular venules, septal veins, and septal arteries. Given that even with meticulous examination
and serial sectioning, vasculitis was not present in
10% of the biopsies, the authors concluded that
vasculitis should not be considered a sine qua non
requirement for histopathologic diagnosis of EI if
otherwise consistent clinicopathologic features are
present.

INFECTION-INDUCED
PANNICULITIS
Etiology and Pathogenesis
Nowhere is an understanding of adipocyte function more important than in appreciating its role
in infectious diseases. As noted in the introduction,
the adipocyte is an innate immune cell, equipped
with surface, transmembrane, and cytosolic PRRs
to deal with and defend against various microbes.
Once TLRs and NLRs are activated, multiple immune response genes participate. These induce the
adipocyte to produce various cytokines, chemokines, and adipokines, thus promoting adaptive immune responses and allowing the full spectrum of
the inflammatory and immune system to target the
site of infection. It appears that the innate immune
system tailors specific and distinct TLR- and NLRmediated transcriptional responses to the various
individual microbial infections.116 With recognition
of the evolution of a significant immune defense
function of the adipocyte, it should come as no
surprise that organisms of all types infect AT, and an
important reason for microbial persistence within
AT is the strategic abilities of organisms to circumvent immune response signaling and to utilize the
intracellular environment to evade the immune
system.117
Adipocytes can be infected in vitro with all types
of organisms, including Chlamydia pneumonia,
CMV, adenovirus, respiratory syncytial virus, influenza,68 MTB,67 Rickettsia prowazekii,69 Trypanosoma
cruzi,70,71,118 Coxiella burnetii,69 and HIV.119,120 In vitro
infection of adipocytes with T. cruzi results in increased expression of multiple proinflammatory cytokines and chemokines, including IL-1, IFN, TNF,
CCL2, CCL5, CXCL10, an increase in TLR2 and TLR9
and acute phase reactants 1 acid glycoprotein
and serum amyloid A3 (SAA3), but a decrease in
adiponectin and peroxisome proliferator-activated
receptor (PPAR), the negative regulators of inflammation.71,121 T. cruzi infects and replicates within
adipocytes both in vivo and in vitro, as adipocytes
are important targets of this parasite.121 Real time
PCR has shown that at 300 days postinfection a
comparable number of parasites are present in
both AT and heart tissue, indicating that AT is a reservoir for the parasites.70,121 AT may serve as a reservoir for Rickettsia prowazekii and MTB.67,69,70 MTB has

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Chapter 70:

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been shown to be present in AT by PCR in EI,5658,122

and as noted in Section Erythema Induratum, once
MTB organisms enter adipocytes, they appropriate
host lipids and survive in a nonreplicating state,
insensitive to isoniazid but sensitive to rifampin and
ethambutol.67 One hypothesis is that access of mycobacteria to O2 is limited in adipocytes, inducing
mycobacterial dormancy. Subsequent to resumption of bacillary growth, bacilli may then serve as a
source for extrapulmonary TB, which accounts for
15% of total TB reactivation cases.67
Studies to date indicate that Mycobacterium leprae
has very limited growth potential in AT. Murine
preadipocytes can be infected in vitro with M.
leprae and bacilli counts can be maintained during
adipocyte differentiation for 3 months using a
three-dimensional in vitro cultural system reconstituting dermis,123,124; however, when the infected
adipose nodules were injected into nude mice,
and incubated in vivo for 3 months, bacilli counts
showed no increase, indicating that preadipocytes
and mature adipocytes were not permissive for M.
leprae multiplication and logarithmic growth.124 By
virtue of their high expression of TLR4, adipocytes
are highly responsive to endotoxin, producing
proinflammatory cytokines at comparable or higher
levels than macrophages.121 TLR2 induction in adipocytes confers a high degree of sensitivity to fungal cell-wall components.121 Liposaccharide (LPS)
injection in the absence of adipocytes in a murine
lipodystrophy model lead to a marked decrease in
systemic IL-6 and SAA3 levels.121 IL-6 is secreted by
adipocytes into the circulation, and a significant
fraction of circulating IL-6 is AT-derived, playing
an important role in host defense mechanism at
times of infections.121 The increase in inflammatory
cytokines from AT is associated with decreased
insulin sensitivity, increased lipolysis, increase in
leptin and decrease in adiponectin, contributing
to metabolic alterations.121 Mutations coding TLRs
or downstream signaling proteins increase infections.125 Point mutations in TLR2 have been associated with higher risks of lepromatous than tuberculoid leprosy.126 TLR4 mutations have been described
that decrease responsiveness to LPS.125,127 Stem cell
transplants from donors with the hyporesponsive
TLR4 variant induced greater susceptibility to aspergillosis in the immunosuppressed recipients.125,128
The genetic variants in TLRs and other innate immune signals and their effect on adipocyte function
and development of panniculitis is not yet known.

CYTOPHAGIC HISTIOCYTIC
PANNICULITIS
Epidemiology
Cytophagic histiocytic panniculitis (CHP) is a rare
panniculitis that varies in duration from 3 months
to 27 years.247,248 Although more common in
adults, it has been described in children, including
one with a perforin gene mutation.53,249 Affected
patients have had systemic and laboratory findings
similar to those found in HPS/hemophagocytic lymphohistiocytosis (HLH) or macrophage activation
syndrome (MAS).

Etiology and Pathogenesis

CHP is considered by some to belong to the spectrum of panniculitides with benign lymphocytic
infiltrate that develop reactive HPS/HLH/MAS.250254
Secondary HPS/HLH disorders are associated
with infections, connective tissue diseases and
malignancies, and can be precipitated by medication.252,255261 The infections associated with HLH/
MAS include EpsteinBarr virus (EBV), CMV, parvovirus, varicella, human herpes virus 6 (HHV6), HHV8,
avian influenza, rubella, adenovirus, hepatitis B, HIV,
bacterial, acid-fast bacterial, parasitic, and fungal
infections.257,262 Primary HLH reactions have been
grouped in the spectrum of autoinflammatory
disease disorders, where impairment of cytolytic
T-cell and NK-cell functions leads to compensatory
mechanisms causing a cascade of reactions that
may result in death.263 Underlying gene mutations
affect vesicular transport, granule shedding, and
pore forming cytolytic proteins involved in granulemediated cytotoxicity. These cytotoxic mechanisms are important in killing of infected cells and
terminating immune responses via apoptosis.262267
Inability of the cytotoxic cells to eliminate infected
cells leads to increased activation and proliferation
of T cells which produce high levels of cytokines
(cytokine storm) that stimulate and activate macrophages without the ability to terminate the reaction via apoptosis.263,264 Animal models of perforin
deficient mice show that infection is needed to
trigger the HLH reaction.262,268 In humans, the same
gene mutations may occur in both primary and
secondary HLH/HPS, but the exact gene and nature
of the gene mutations (nonsense vs. missense
mutations) may affect the phenotype and age at

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Chapter 70: Panniculitis 63

presentation.262,269 Primary and secondary HLH are

similar and the distinction may be artificial.269 The
reason for the presence of the lymphohistocytic
inflammation in the AT in CHP in the first place is
unknown, but it is probable that the function of the
adipocyte as an innate immune cell and its special
relationship with CD8+ T cells has a central role in
this development.
Some suggest that all CHP cases represent undetected cases of SPTL.214,270 Immunophenotyping and
genotyping studies are important for differentiating two forms of malignant SPTL, (1) SPTL-AB (
rearranged T cells) and (2) SPTL-GD ( gene rearranged T cells), from CHP with benign T cells. Multiple biopsies may need to be taken over time to ensure that the lymphocytes are benign, since there
are reports of progression from benign-appearing
histopathology to the malignant SPTL.271 Both SPTLAB and SPTL-GD cases can be associated with HPS/
HLH and present with CHP.216 The incidence of HPS/
HLH was much higher among SPTL-GD cases than
in SPTL-AB cases (45% vs. 17%).216

Clinical findings
Lesions are subcutaneous plaques and nodules
of variable sizes that may coalesce on the extremities and trunk and less frequently on the head and
neck.247,251,253,254 (Fig. 70-14A). Features may vary
from skin color to erythematous, purpuric, ecchymotic, or hyperpigmented; flat or raised; well circumscribed or diffuse; and indurated to fluctuant or
ulcerated.251,253 Persistent drainage after biopsy may
occur.251,253 More fulminant forms of the disease
may be associated with persistent fever, hepatosplenomegaly, lymphadenopathy, serosal effusions,
pancytopenia, intravascular coagulation, liver failure, hemorrhagic diathesis, and death.251,253,248,271
At a minimum, laboratory tests should include
CBC with differential, liver functions, ferritin, sedimentation rate (ESR), and lipid profile. A decreasing
ESR most likely indicates decreasing fibrinogen and
development of disseminated intravascular coagulopathy (DIC).257,263 Soluble hemoglobin-haptoglobin scavenger receptor CD163 levels in serum are
closely associated with hemophagocytic disease
activity and correlate with serum ferritin, and are
much higher (median 39.0 mg/L) than levels seen
in sepsis (median 8.2 mg/L) and in normal controls
(median 1.8 mg/L).272 Other tests are determined
by history and physical findings, results of initial

workup, and the clinical course. When CHP is found,

it is imperative to consider a diagnosis of SPTL and
at the same time to search for connective tissue
disorders and infections. Essential in guiding the
infectious disease workup are geographic location
of the patient and travel history.

Histopathological Findings
Biopsy of lesions should be deep and large and include the whole layer of subcutaneous tissue; more
than one biopsy may be needed to establish the
diagnosis of CHP as evidence of cytophagocytosis
may be focal. Although septal involvement may be
seen, the histopathology is principally that of a lobular panniculitis (Fig. 70-14B) with fat lobules containing an infiltrate of histiocytes (macrophages)
and mature lymphocytes; admixed plasma cells,
neutrophils, and eosinophils are variably present.
Phagocytic histiocytes contain intact or fragmented
red cells, white cells, platelets, and nuclear debris
within their cytoplasm; macrophages packed with
these elements represent the characteristic beanbag cells (Fig. 70-14C). Often, there is considerable
necrosis of the adipocytes of the fat lobule, which
may be accompanied by hemorrhage. Immunohistochemical studies demonstrate that histiocytes
with cytophagic activity express histiocytic markers
such as CD68, whereas most of the lymphocytes
show a T-cell immunophenotype. The presence of
atypical lymphocytes is suspicious for lymphoma.273
In reactive, non-SPTL associated CHP, molecular
genetic studies fail to demonstrate monoclonality
of the lymphoid cells. In rapidly progressive cases
of CHP associated with HLH, cytophagic features
can also be seen in internal organs, including lymph
nodes, spleen, liver, and bone marrow, and in CSF
fluid.247,248,251,253,271

Prognosis/Clinical Course
Patients may have a rapidly fatal disease course, a
longer disease course with intermittent remissions
and exacerbations for many years prior to death, or
a nonfatal acute or intermittent course responsive
to treatment.248,253,271,274 Patients with the benign,
nonfatal course were found to have less significant
laboratory abnormalities.274

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Chapter 70:

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COLD PANNICULITIS

Treatment
Because CHP can be associated with a rapidly fatal
course, it is essential to use a team approach with
input from an infectious disease specialist, rheumatologist, and hematologist. Hospitalization may be
required for a rapid workup and institution of treatment. In HLH associated with infection, pathogendirected therapy may result in high incidence of
recovery269; the cytokine storm seen in EBV-associated HPS/HLH is more pronounced, and may be less
responsive to treatment.269 Even prompt identification and treatment of an associated infection may
not arrest the progression of a rapidly evolving HPS/
HLH.269 Treatment of CHP must decrease cytokine
release by activated lymphocytes, adipocytes, and
macrophages and abate the cytokine storm which
can lead to a fatal HLH cascade. This means using
immunosuppressive, immunomodulating, or cytotoxic agents that target activated macrophages/
histiocytes (steroids, etoposide, high-dose IVIG)
and T cells (steroids, cyclosporine A, antithymocyte
globulin).268 Treatments in some CHP patients have
included prednisone, cyclosporine, and combined
chemotherapeutic regimens, alone or followed by
cyclosporine.248,275 Treatment is difficult and imperfect, although skin lesions have responded better
to immunosuppressive (vs. cytotoxic) therapy.248
A case of SLE-associated CHP had only temporary
remission with prednisone and cyclosporine, but
was successfully treated with IV pulse cyclophosphamide and IVIG.220 One patient with CHP had an
initial brief response to cyclosporine followed by
progression and death with generalized HLH in
spite of persistent resolution of the CHP lesions.276
In nonpanniculitis-associated HPS HLH, the
Histiocyte Society recommends etoposide and
dexamethasone in combination with cyclosporine.277 Considering the similarities of CHP and HLH,
and the response of many of the CHP patients to a
protocol combining prednisone, cyclosporine, or
addition of combined chemotherapeutic options
(i.e., CHOP), following the HLH treatment recommendations may be warranted.254
One adolescent with lifelong recurrent febrile
lymphocytic cytophagocytic panniculitis experienced reversal of the daily fever and other signs of
HPS with anakinra, an IL-1R antagonist, in addition
to prednisone and cyclosporine.278

Cold panniculitis is an inflammatory reaction in

AT that occurs after skin exposure to cold weather
and ice application (as in cold pack application for
supraventricular tachycardia), and can occur on mucosae after exposure (popsicle panniculitis).307309
The involved areas appear as erythematous to
purplish indurated nodules, plaques, or swellings in
the cheeks or the submental area of a child,308 1 to 2
days following cold exposure, and disappear within
2 weeks to 3 months,308 although postinflammatory
hyperpigmentation may remain.309
Scrotal cold panniculitis, also known as scrotal
fat necrosis, occurs in prepubertal (914-year-old)
heavy-set or obese boys after cold exposure (including swimming in cold ocean water). It manifests
as unilateral or bilateral tender masses below the
testes. Recognizing these changes as cold panniculitis is important in order to avoid unnecessary
biopsy intervention, as spontaneous resolution
over days to several weeks will occur. Ultrasound
findings are helpful in confirming this diagnosis.310
Scrotal cold panniculitis is thought to be related to
the greater concentration of scrotal fat and the increased cold sensitivity of the types of fats present
in the scrotal AT of boys.311,312
Adolescent and adult women who participate
in outdoor sports in cold damp conditions can
develop thigh lesions; this condition is commonly
referred to as equestrian panniculitis.313,314 Appearing some hours after long outdoor cold exposure
while wearing tight-fitting, noninsulated pants,
the lesions are pruritic red violaceous nodules and
plaques that may focally ulcerate or crust.308 The
condition resolves with cold avoidance, or after the
end of the sports activity season,53,308 or with wearing of looser trousers with insulating undergarments. Equestrian panniculitis may represent perniosis/chilblains, rather than a true panniculitis.315,316
High levels of cold agglutinins were detected in
two affected Scottish women.315
In general, the histologic picture in cold panniculitis is that of a mostly lobular panniculitis, with a
lymphohistiocytic or mixed inflammatory infiltrate
present within fat lobules.53 Variably seen is an
overlying superficial and deep perivascular lymphocytic infiltrate with prominent inflammation of
veins most notable at the dermalsubcutaneous
fat junction; these histopathologic findings closely

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Chapter 70: Panniculitis 65

resemble those seen in perniosis.53,98,314

In affected infants, the mechanism of inflammation has been attributed to a higher proportion
of saturated fat in infants, with the composition
becoming more unsaturated with age.308,309,312 Other
mechanisms may also be involved, including the
effects of cold on BAT, which is more prevalent in
infants than adults, and its activation to generate
heat, since babies cannot rely on shivering alone
for adequate heat generation.25,291 Cold exposure
leads to a number of changes in BAT, including
an increase in vascular endothelial growth factor
(VEGF), enhanced free fatty acid degradation, and
metabolic changes.317319 Under circumstances in
which rapid adaptation to the cold is aberrant, this
may result in an inflammatory reaction mediated by
AT cytokines. Cryoglobulins and cold agglutinins do
not play a role.309
Distinguishing cold panniculitis from SCFN is
important, since SCFN has been reported to occur
following the application of cold packs to a neonate,
and it may have complications such as hypercalcemia, whereas cold panniculitis is not associated
with such complications.286

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