Chapter 34 :: Granuloma Annulare

:: Julie S. Prendiville
AT-A-G LANCE
■ Granuloma annulare is a relatively common disorder. The
exact prevalence is unknown, but it occurs more often in
children and young adults.
■ A localized ring of beaded papules on the extremities is
typical; generalized, subcutaneous, perforating, and patch
Pa subtypes also occur.
rt
■ The cause of granuloma annulare is unknown, and the
5 pathogenesis is poorly understood.
Li ■ Pathologic features consist of granulomatous inflammation
ch in a palisaded or interstitial pattern associated with varying
e degrees of connective tissue degeneration and mucin
deposition.
n arcuate lesion. It may be skin colored, erythematous, or
oi ■ Most localized cases resolve spontaneously within 2 years.
d annular margin is firm to palpation and may be continuous or
an
d Granuloma annulare is a benign self-limited disease that was
Gr first described by Colcott-Fox in 1895 and Radcliffe-Crocker 1 in
an 1902.
ul
o
m
EPIDEMIOLOGY
at Granuloma annulare is a relatively common disorder. 2 It occurs
o in all age groups but is rare in infancy. 2"4 The localized annular
and subcutaneous forms occur more frequently in children and
young adults. The generalized or disseminated variant is more
common in adults. Many studies report a female
preponderance,2 but some have found a higher frequency in
males.5 Granuloma annulare does not favor a particular race or
geographic area.
Most cases of granuloma annulare are sporadic. Occasional
familial cases are described with occurrence in twins, siblings,
and members of successive generations. 2,6'7 Attempts to identify
an associated human leukocyte antigen subtype have yielded
disparate results in different population groups.
CLINICAL FEATURES
HISTORY
The typical history is of one or more papules with centrifugal
enlargement and central clearing. These annular lesions are
often misdiagnosed as tinea corporis and treated unsuccessfully
with topical antifungal agents. Subcutaneous nodules may raise
suspicion about malignancy or rheumatoid disease.
CUTANEOUS FINDINGS
Clinical variants of granuloma annulare include the localized,
generalized, subcutaneous, perforating, and patch types. Linear
granuloma annulare, a follicular pustular form, papular
umbilicated lesions in children, and giant plaques have also
been described. There is overlap among the different variants,
and more than one morphologic type may coexist in the same
patient.
LOCALIZED TYPE
The most common form of granuloma annulare is an annular or
violaceous. It usually measures 1 to 5 cm in diameter. 2 The
consist of discrete or coalescent papules in a complete or partial
circle (Fig. 34-1). The epidermis is usually normal, but surface
markings may be attenuated over individual papules. Within the
annular ring, the skin may have a violaceous or pigmented
appearance. Solitary firm papules or nodules may also be
present. Papular lesions on the fingers may appear umbilicated.
The dorsal hands and feet, ankles, lower limbs, and wrists are
the sites of predilection (see Figs. 34-1 and 34-2). Less
commonly, lesions occur at other sites, including the eyelids.
The palms and soles are occasionally involved. Localized
annular lesions may coexist with the subcutaneous or patch
forms.
GENERALIZEDTYPE
The generalized form of granuloma annulare is said to comprise
8% to 15% of cases.8 The majority of patients are adults, but it
may also be seen in childhood. Unlike in localized disease, the
trunk is frequently involved in addition to the neck and
extremities. The face, scalp, palms, and soles may also be
affected.
Generalized granuloma annulare presents as widespread
papules (Fig. 34-3A), some of which coalesce to form small
annular plaques or larger discolored patches with raised arcuate
and serpiginous margins (see Fig. 34-3B). Lesions may be skin
colored, pink, violaceous, tan, or yellow. An annular or
nonannular

Granuloma annulare is usually asymptomatic. Mild pruritus

may be present, but painful lesions are rare. Nodular lesions on
the feet may cause discomfort from footwear. Cosmesis is often
a concern for adolescent and adult patients, particularly with
generalized disease.
 perforating granuloma annulare has also been described.

SUBCUTANEOUSTYPE

Ch
ap
ter
34
::
Gr
an
ul
o
m
a
An
Figure 34-1 A, Typical annular lesion of granuloma annulare on nu
a finger. B, A larger annular lesion of granuloma annulare on Figure 34-3 A, Generalized granuloma annulare. Small papular
the dorsum of the hand. lesions that are too small to exhibit annular configuration. B,
Multiple annular lesions on the lower arm.

The subcutaneous form of granuloma annulare occurs

predominantly in children9'10 but is also described in adult
patients. It is characterized by

Figure 34-2 Localized granuloma annulare with nodule on the

hand of a child.

56
5
 firm to hard, usually asymptomatic nodules located in the deep
dermis and subcutaneous tissues. They may extend to
underlying muscle, and nodules on the scalp and orbit are often
adherent to the underlying periosteum.
Individual lesions measure from 6 mm to 3.5 cm in diameter.
They are distributed most often on the anterior lower legs in a
pretibial location. Other sites of predilection are the ankles,
dorsal feet, buttocks, and hands. Nodules on the scalp, eyelids,
and orbital rim may present a diagnostic challenge. Sub-
cutaneous granuloma annulare may also be found on the penis.

PERFORATING TYPE
The perforating type of granuloma annulare is a rare variant
characterized by transepidermal elimination of the necrobiotic
collagen. It may be localized, usually to the dorsal hands and
fingers (Fig. 34-4), or generalized over the trunk and
extremities. It has been described on the ears, on the scrotum,
and within herpes zoster scars and tattoos. Superficial small
papules develop central umbilication or crusting, and there may
be discharge of a creamy fluid. Lesions heal with atrophic or
hyperpigmented scars. In one series, 24% of patients
complained of pruritus and 21% of pain. Papular umbilicated
granuloma annulare on the hands of

56
6
 children and a generalized follicular pustular type of granuloma
annulare may be clinical variants.
Pa Figure 34-4 Granuloma annulare on the knuckles of a dark-
skinned patient. (Image used with permission from the Graham
rt
Library of Wake Forest Department of Dermatology.)
5 these cases. However, in other instances, generalized granuloma
Li
ch
e PATCH TYPE
n vaccination have been implicated as triggering factors, although
oi Macular lesions that present as erythematous, red- brown, or
d violaceous patches without an annular rim are reported in adult
women.11 An arcuate dermal erythema is also observed.
an
d Most patients with granuloma annulare are healthy and have no
Gr other abnormal physical findings. Arthralgia is reported in
an association with painful lesions on the hands. 12 Granuloma
ul
o which chronic relapsing granuloma annulare flared during
m NONCUTANEOUS FINDING
at
o annulare-like skin lesions and joint disease characterize a
multisystem disorder described as interstitial granulomatous
dermatitis with arthritis.13
Oral involvement has been observed in HIV-associated
disease.14
ETIOLOGY AND
PATHOGENESIS
The etiology of granuloma annulare is unknown, and the
pathogenesis is poorly understood. Most cases occur in
otherwise healthy children. A variety of predisposing events and
associated systemic diseases is reported, but their significance is
unclear. It is possible that granuloma annulare represents a
phenotypic reaction pattern with many different initiating
factors.
PREDISPOSING EVENTS
Nonspecific mild trauma is considered a possible triggering
factor because of the frequent location of lesions on the distal
extremities of children. An early study of subcutaneous
granuloma annulare found a history of trauma in 25% of
children,2 but this observation has not been replicated. Trauma
is also a suspected factor in auricular lesions. Granuloma
annulare has occurred after a bee sting, a cat bite, and an
octopus bite, and insect bite reactions have also been
implicated.2 There is a report of perforating granuloma annulare
in longstanding tattoos. Widespread lesions have developed
after waxing-induced pseudofolliculitis and erythema
multiforme minor and in association with systemic
sarcoidosis.2,15 Severe uveitis without other evidence of
sarcoidosis has occurred in a few patients with granuloma
annulare.16-18
INFECTIONS AND IMMUNIZATIONS
There are several reports of the development of granuloma
annulare within herpes zoster scars, sometimes many years after
the active infection. It is also described after chickenpox.
Generalized, localized, and perforating forms of granuloma
annulare may occur in association with HIV infection.
Adenovirus was isolated from a lesion in one HIV-positive
patient. Epstein-Barr virus was excluded as a causative agent in
annulare has been linked to viral infections, including Epstein-
Barr virus infection, chronic hepatitis B, and hepatitis C.
Vaccinations for tetanus, diphtheria toxoid, and hepatitis B
vaccination sites were spared in one case of generalized
granuloma annulare.19
Lesions compatible with granuloma annulare may occur in
patients with active tuberculosis. There are also reports of
granuloma annulare after tuberculin skin tests and bacille
Calmette-Guerin immunization. Evidence of Borrelia
burgdorferi infection was detected in two reports, but this
association was not confirmed in a serologic study. A case in
scabies infestation was attributed to the Koebner phenomenon. 20
SUN EXPOSURE
Granuloma annulare with a predilection for sun- exposed areas
and seasonal recurrence has been described. Photosensitive
granuloma annulare has been observed in patients with HIV
infection.14 Generalized disease after psoralen plus ultraviolet A
(UVA) light therapy is reported, but it is of note that photo-
therapy and PUVA phototherapy have been used to treat
generalized granuloma annulare.21-23
Actinic granuloma, also known as annular elastolytic giant
cell granuloma, develops on photodamaged skin and is believed
to represent a granulomatous reaction to actinic elastosis.24 Its
relationship to granuloma annulare is debated.
DRUGS
Granuloma annulare-like drug reactions are reported for gold
therapy and treatment with allopurinol, diclofenac, quinidine,
intranasal calcitonin, topiramate,
amlodipine, and granulomatous drug reaction
thalidomide.25 There are also linked to the use of
reports of an association with angiotensin-converting
adalimumab, infliximab, enzyme inhibitors, calcium
etanercept, efalizumab, and channel blockers, and other
vemurafinib.22-23-25 medications is considered a
An interstitial distinct entity but may mimic
56
7
 granuloma annulare.26-27 leukemias and with annulare rarely predates the
DYSLIPIDEMIA
onset of diabetes. The his-
solid tumors, topathologic similarity An increased prevalence of
particularly of the between granuloma annulare dyslipidemia has been
breast. The skin and necrobiosis lipoidica reported in patients with
lesions of diabeticorum and the coexis- granuloma annulare.32 This
tence of both conditions in was more commonly found in
cutaneous occasional diabetic patients generalized granuloma
lymphoma and suggest a true association. annulare, particularly in cases
other hematologic However, most patients with with an annular morphology.
malignancies can granuloma annulare do not
have diabetes mellitus.
mimic granuloma
annulare both
Studies attempting
establish a causal correlation
to LABORATOR
clinically and have yielded conflicting Y TESTS
histopathologically. results.22
Granuloma annulare has A diagnosis of localized
It may be difficult granuloma annulare is made
also occurred in a number of
to distinguish patients with thyroiditis, on clinical examination, and
whether they hypothyroidism, and thyroid further evaluation is rarely
represent true adenoma.22 indicated. Biopsy to obtain a
specimen for histopathologic
granuloma
examination is necessary
annulare with MALIGNANCY when the presentation is
atypical atypical, when lesions are
An association between
lymphocytes or granuloma annulare and
symptomatic, and when the
cutaneous diagnosis is otherwise in
mahgnancy in adult patients
doubt. Histopathologic
lymphoma is reported primarily with
analysis may be required to
obscured by a Hodgkin and non-Hodgkin
confirm a diagnosis of
lymphoma, including mycosis
granulomatous fungoides, Lennert
generalized granuloma
infiltrate.31-32 annulare or subcutaneous
lymphoma, B-cell disease, T-
nodular disease on the head
cell leukemia and lymphoma,
and orbital region.
PATHOGENIC SYSTEMIC and angioblastic T-cell
lymphoma. It is reported less
MECHANISM DISORDERS commonly with myeloid
AND HISTOPATHO Ch
The pathogenic mechanisms
that result in foci of altered GRANULOM LOGIC ap
connective tissue surrounded
by a granulomatous
A ANNULARE FINDINGS
ter
34
inflammatory infiltrate are ::
not understood. Proposed DIABETES The diagnosis is best made at Gr
mechanisms include (1) a low magnification. Changes
primary degenerative process
MELLITUS AND are usually observed in the
an
ul
of connective tissue initiating THYROID DISEASE upper and middle dermis,
o
granulomatous inflammation, although any part of the
Development of granuloma m
(2) a lymphocyte-mediated dermis or subcutis can be
annulare in patients with a
immune reaction resulting in involved. The characteristic
diabetes mellitus is An
macrophage activation and histopathologic finding is a
extensively documented.
cytokine-mediated lymphohistiocytic granuloma nu
Whether this is a true
degradation of connective associated with varying
relationship has long been
tissue, and (3) a subtle degrees of connective tissue
debated. The link is primarily
vasculitis or other degeneration and mucin
with type 1 insulin-dependent
microangiopathy leading to deposition. The inflammatory
diabetes, but cases are also
tissue injury.28-30 infiltrate may have a
reported with type 2 non-
palisaded or interstitial
insulin- dependent disease.
pattern or a mixture of both
Localized and generalized as
patterns.33-35 Occasionally, a
well as subcutaneous nodular
sarcoid-like pattern with large
and perforating forms of
epithelioid histiocytes is seen.
granuloma annulare have
The typical appearance is
been observed. Granuloma
of single or multiple foci of

56
8
inflammation with a central
core of altered collagen
(necrobiosis) surrounded by a
wall of palisaded histiocytes
(Fig. 34-5). The necrobiotic
centers are usually oval,
slightly basophilic, devoid of
nuclei, and marked by a loss
of definition of the collagen
bundles and diminished or
absent elastic tissue fibers.
Stains for mucin and lipid
often give positive results.36
An interstitial,
nonpalisaded pattern of
inflammation with histiocytes
infiltrating among fragmented
collagen bundles may be
predominant, particularly in
the generalized form. This
interstitial pattern is also
observed in the absence of
apparent connective tissue
change. Stains for mucin may
be helpful in detecting
connective tissue alteration
within the infiltrate.

56
9
 Lymphocytes are admixed
with histiocytes in the
granuloma and in a They may be distinguished
Pa
rt Figure 34-5 Palisading granulomatous inflammation sur-
5 rounding degenerating collagen within the dermis.
Li (Hematoxylin and eosin stain, x200.) (Used with permission
ch from Dr. Richard Crawford.)
e
n perivascular distribution.
Multinucleated giant cells
oi
may be present but are not as
d
numerous as in actinic
an granuloma.37 Neutrophils and
d eosinophils are occasionally
Gr seen, but plasma cells are
an rare. Evidence of vascular
ul reactivity includes variable
o endothelial cell swelling, red
m cell extravasation, fibrin,
at leukocytoclasis, and
neutrophilic infiltration in
o
blood vessel walls. When
leukocytoclastic vasculitis or
nuclear debris is a prominent
finding, a diagnosis of
palisaded neutrophilic and
granulomatous dermatitis of
immune complex disease
should be considered.38
In subcutaneous
granuloma annulare (Fig. 34-
6), the foci of necrobiosis are
Figure 34-6 Subcutaneous granuloma annulare pathology. (Used
with permission from the Graham Library of Wake Forest
Department of Dermatology.)
57
0
larger and lie within the deep
dermis and subcutaneous fat.
from rheumatoid nodules by
the presence of mucin in the
necrobiotic zone. Central
ulceration and
communication between the
area of necrobiosis and the
surface are characteristic of
perforating granuloma
annulare (Fig. 34-7).
Examination of serial sections
may be necessary to
demonstrate the necrobiotic
plug. An interstitial pattern of
inflammation with diffuse
necrobiosis is reported in the
patch type of granuloma
annulare. Palisaded
granulomas have also been
observed in macular lesions.
Immunofluorescence
testing may show deposition
of fibrin, immunoglobulin
(Ig) M, and C3 as a variable
finding around vessel walls or
at the basement membrane granuloma annulare.
zone; IgM cytoid bodies are Investigation for endocrine
also reported.39 disease is indicated if the
Figure 34-7 A and B, Histopathology of perforating granuloma
annulare. (Used with permission from the Graham Library of
Wake Forest Department of Dermatology.)
Immunohistochemistry may patient has signs or symptoms
be useful to confirm the of diabetes or thyroid
histiocytic nature of dysfunction. Lipid studies
equivocal disease. may be considered in the
Ultrastructural changes in the evaluation of generalized
connective tissue and granuloma annulare.32
capillaries have been Imaging studies may be
described.40 performed in subcutaneous
granuloma annulare when the
A diagnosis of granuloma
clinical features are not
annulare is made clinically or
recognized or when the
SPECIAL TESTS
presentation is atypical with
by skin biopsy. Special
rapid enlargement or pain.
investigations are usually not
Radiographs show a non-
necessary. Further evaluation
specific soft tissue mass
to rule out systemic disease
without calcification or bone
such as infection, sarcoidosis,
involvement.
or malignancy may be
Ultrasonographic
required in atypical cases of
examination reveals
TABLE 34-1 Annular Type
Differential Diagnosis of Consider
Granuloma Annulare ■ Tinea corporis
■ Subacute cutaneous lupus
erythematosus
■ Neonatal lupus erythematosus
■ Annular lichen planus
■ Acute febrile neutrophilic
dermatosis
■ Erythema chronicum migrans
■ Actinic granuloma/annular
elastolytic giant cell granuloma
■ Necrobiosis lipoidica
diabeticorum
Rule Out
■ Infections (eg, tuberculosis,
atypical mycobacteria, syphilis)
■ Interstitial granulomatous
dermatitis with arthritis
■ Interstitial granulomatous drug
reaction
■
■
Annular sarcoidosis
Lymphoma
Generalized Type
Consider
■ Lichen planus
■ Lichen nitidus
■ Molluscum contagiosum
Rule Out
■ Lichenoid and granulomatous
dermatitis of acquired
immunodeficiency syndrome
■ Infections (eg, tuberculosis,
atypical mycobacteria, syphilis)
■ Sarcoidosis
■ Blau syndrome (familial
granulomatous arthritis, skin
eruption, and uveitis)
■ Interstitial granulomatous drug
reaction
■ Lymphoma
Subcutaneous Type
Consider
■ Erythema nodosum
■ Dermoid cyst
■ Rheumatoid nodules
Rule Out
■ Epithelioid sarcoma
■ Benign or other malignant
tumors
■ Deep infections
Perforating Type
Consider
■ Molluscum contagiosum
■ Insect bites
■ Pityriasis lichenoides
■ Perforating collagenosis and
other perforating disorders
■ Foreign body granuloma
■ Papulonecrotic tuberculid
■ Palisaded neutrophilic and
granulomatous dermatitis of
immune complex disease
Patch Type
Consider
■ Morphea
■ Erythema annulare centrifugum
■ Parapsoriasis
Rule Out
■ Lymphoma
a hypoechoic area in the ■ Other
subcutaneous tissues.41-42 ■ Phototherapyd
Magnetic resonance imaging ■ Photodynamic therapy
■ Fractional
shows a mass with indistinct
photothermolysis
margins, isointense or slightly
Skin biopsy
hyperintense to muscle with ■ Cryotherapy
Tl-weighted images and with ■ Pulsed dye, Excimer,
a heterogeneous but Nd:YAG or CO laser
predominantly high signal V ___________________
intensity on T2-weighted "Application of 5% imiquimod
cream has been reported to worsen
images.41-43
granuloma annulare in a child.
triple antibiotic regimen (rifampicin,
DIFFERENTIA ofloxacin, minocycline), doxycycline,
antituberculosis therapy.
'Development of granuloma
L DIAGNOSIS annulare has been reported during
therapy with etanercept, infliximab,
See Table 34-1. and adalimumab.
Narrowband ultraviolet B,
d
ultraviolet Al, psoralen plus
TREATMENT ultraviolet A.
Nd:YAG, neodymium-doped yttrium
The usual treatment options aluminum garnet.
include awaiting spontaneous
resolution, topical steroids,
and intralesional steroids.
These and various other
therapies of anecdotal benefit
are summarized in Table 34-
2. Most
TABLE 34-2
Treatment Options for
Granuloma Annulare
■ Await spontaneous
resolution
■ Apply topical corticosteroid
with or without occlusion
■ Administer intralesional
triamcinolone 2.5 mg/mL
Anecdotal Reports of Benefit
■ Topical
■ Tacrolimus 0.1% ointment
■ Pimecrolimus cream
■ Imiquimod 5% cream3
■ Intralesional
■ Interferon-y
■ lnterferon-p
■ Sterile water or saline
■ Systemic
■ Antimalarials
■ Retinoids
■ Antibioticsb
■ Corticosteroids
■ Cyclosporine
■ Zileuton with vitamin E
■ Fumaric acid esters
■ Pentoxifylline
■ Hydroxyurea, chlorambucil,
niacinamide, potassium
iodide, dapsone
■ Etanercept
■ Infliximab'
■ Efalizumab'
■ Adalimumab'
57
1
 treatment recommendations Martinon- Sanchez F. uveitis with retinal drug reaction with a
are based on single case Localized granuloma vasculitis? Br J histological pattern of
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Paediatr. 1999;158:866. 17. Brey NV, Purkiss TJ, Dermato- pathol. 2001 ;
studies.21-23,44-47
6. Friedman SJ, Sehgal A, et al. 23:295.
Winkelmann RK. Association of 28. Dahl MV. Speculations
Familial granuloma inflammatory eye disease on the pathogenesis of
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2
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