NODULAR LESIONS OF
THE SKIN.
Granuloma.
Tick bite
Tick bite is always responsible for
a cutaneous lesion. The latter ranges from an
inflammatory papule to a granulomatous lesion, till to a
gangrenous and then ulcerated lesion of various size.
Other manifestations can be associated to tick bite such
as those ones caused by toxic products of the tick
(ascending flaccid palsy), the reactive manifestations
against tick allergens and, finally, the manifestations
caused by the tendency of the tick to be carrier of
infectious agents of various type such as viruses,
rickettsiae and spirochetae. However, we are not dealing
in this chapter with the cutaneous and extracutaneous
manifestations associated with tick bite.
The tick is a mite. Its body can be covered by a hard
shield as in the family Ixodidae. The life cycle of the
tick passes through four stages (eggs, larvae, nymphs and
adults).
Except for the stage of eggs, ticks need hematic meals.
Particularly, the adult female needs hematic meals before
laying eggs. The human is an occasional host, whereas
wild animals are the usual host.
The tick wait for its host in the vegetation. When with
its sense organs the tick notices the presence of the
host, then rapidly attaches to its fur, introduces its
toothed rostrum into the skin of the host and starts
eating. The latter can last for some days in the case of
Ixodidae ticks. The meal can last for a so long period of
time because the tick is not always visible, for instance
when localized on the scalp (Fig. 759).
 Fig. 759
In the latter case the child can
complain of only persistent headache.
Moreover, even in visible sites the tick filled in with
blood can be misdiagnosed as a wart or another
neoformation and should be removed by the physician.
Removing the tick is not easy because the teeth of the
rostrum are oriented at acute angle towards the surface
of the epidermis. Numerous techniques of remowal were
reported. This is probably related to the lack of an
appropriate technique. Usually, it is enough seizing with
pliers the tick as close as possible to the surface of
the epidermis and pull up gradually without abrupt jerks.
From a clinical
point of view, the most frequent cutaneous lesion is a
gross inflammatory papule or nodule (Fig. 758).
However, sometimes we are dealing with a 2-4 centimeters
in size eschar (Fig. 760), which is later followed by an
ulcer with clear-cut edges (Fig. 761). In the latter case
the lesion heals with an alopecic scar. On the scalp,
besides the scarring alopecia, a perilesional, transitory
alopecia may be present. Almost invariably, the regional
lymph nodes are enlarged, firm and sometimes painful.
The local treatment consists of antibiotic creams in case
of eroded or ulcerated lesions and corticosteroid
ointments when facing papular or nodular lesions.
Pseudolymphoma
Although less frequent than in
young adults, even in children there are plaques or
persistent inflammatory nodules, isolated (Fig. 762, 763)
or multiple, scarcely symptomatic, which undergo slow,
spontaneous regression within many months.
On light microscopy, there is a massive lymphocytic
infiltrate in the whole dermis, sometimes associated to
the presence of germinal centres.
The immunohistochemical phenotyping usually shows a
B-lymphocyte infiltrate. However, T-lymphocytes may be
the main component of the infiltrate. The possible
follicular distribution of the infiltrate and a low
mitotic index help in differentiating this disorder from
a true lymphoma.
From an etiologic point of view, a persistent antigenic
stimulus can be hypothesized. The latter probably follows
insect stings, similarly to the cutaneous nodules caused
by Sarcoptes scabiei or ticks.
Topical corticosteroid ointments are indicated as local
treatment.
Artefact
granuloma
These lesions follow repeated
movements, usually aimed at discharging the nervous
tension. Therefore, these granulomas have the same
innocent significance of a tic. Artefact granulomas are
much more severe in the cerebropathic children.
Artefact granulomas are usually observed on the dorsal
aspect of the hands, due to repeated chewing or pinching
of the skin.
From a clinical point of view, artefact granuloma appears
as a brownish, firm nodule (Fig. 764) of about one
centimeter in size.
The tic is not always reported by the patient. Therefore,
physicians should clinically suspect the pathogenetic
mechanism and receive confirmation by the patients or
their relatives.
Withdrawing the repeated trauma is followed by the
regression of the lesions after many months. Withdrawing
can be easily achieved, when explaining to the patient
the pathogenetic mechanism of the lesions.
Granuloma
due to injection of oily excipients
The injection in the buttocks or
thighs of drugs in oily excipients can give raise to
foreign body granulomas (Fig. 765). The latter may arise
a very long period of time after the injection and
persist for months or years. Moreover, this granuloma may
arise at distance from the injection, due to sliding of
the oily excipients. Surgical removal is sometimes the
only therapeutical option for this disorder.
Granulomatous
calcinosis of the skin
The introduction of calcium salts,
especially calcium gluconate, into the skin can be
responsible for this granuloma. Calcium gluconate has
been used in the past in various disorders, ranging from
tetany to hemorrhagic syndromes, smooth muscle spasms,
allergic conditions, jaundice and such infectious
diseases as tuberculosis and gonorrhea. Moreover,
intravenous calcium gluconate is routinely used in the
neonate, especially if premature, whenever partial or
total parenteral feeding is required.
However, calcium therapy is not free from side effects,
which have been described almost exclusively in the
newborn, probably because early or late hypocalcemia is
relatively more common in the neonate and especially in
the premature neonate.
The use of calcium gluconate is practically restricted to
the intravenous route. However, even on intravenous
infusions calcium gluconate proved capable of giving rise
to calcinosis, due to accidental extravasation of the
solution at the site of the injection. As the calcium
gluconate solution is not radio-opaque, the radio-opaque
deposits, which can be detected with a radiography of the
soft tissue, consist of calcium phosphate. As 10%
solution of calcium gluconate is supersaturated,
crystallization may be the first step in the formation of
calcium deposits. Tissue trauma, bleeding, infectious
factors and hyperphosphoremia associated to neonatal
tetany probably contribute to the deposit formation of
calcium salts.
From a clinical point of view, the extravasation of
calcium gluconate can be immediately followed by an acute
dermohypodermitis, which is characterized by infiltrated
yellowish areas.
In other cases the extravasation is not immediately
followed by visible lesions and only some weeks later
hard, granulomatous lesions (Fig. 766) develope, which
are covered by normal skin.
The inflammatory
cases should be differentiated from myositis ossificans
and infectious dermohypodermitis. When there is no
inflammation, other granulomas and osteoma should be
ruled out. Even the radiological findings can be
misdiagnosed. Calcium gluconate not being radio-opaque,
calcium deposits (Fig. 767) become demonstrable on
average some two weeks from the start of treatment. The
area of calcification may be found at the injection site,
as an amorphous mass which mimics myositis ossificans or,
if close to the bone, periostitis. The calcification may
be more extensive, less radio-opaque, granular and may
mimic the picture found in children with calcifying
dermatomyositis or, finally, the calcifications may be
distributed around the vascular and neural structures. On
light microscopy, the epidermis may show slight
acanthosis and parakeratotic hyperkeratosis, it may also
appear thin with more or less evident areas of necrosis,
especially in segments covering calcium deposits in the
papillary dermis. The dermis may show evidence of
degeneration of collagen fibers with calcium deposits in
the form of an amorphous mass, sometimes surrounded by
lymphohistiocytic infiltration with several giant cells.
In early stages the inflammatory infiltrate may be more
prominent. The calcifications regress spontaneously
within 4-8 weeks. A local antiinflammatory corticosteroid
treatment may be useful in the inflammatory cases.
Foreign
body granuloma
A foreign body granuloma may follow
the accidental introduction into the skin of vegetal
(cactus, rose) or animal (urchin) thorns. The latter are
the most frequent during summertime in children and
adolescents. Immediately after the sting, which usually
occurs on the palmar and plantar region, and on the
extensor aspect of the elbows and knees, a burning
sensation occurs and lasts for some hours. The thorns
should be removed with a sterile needle, after immersion
in water for several minutes of the site affected, to
soak the horny layer. If the thorns are not removed, a
foreign body granuloma arises, which may last till two
years. Corticosteroids injected into the granulomatous
lesions may shorten the reabsorption time of the
granuloma.
The dermal foreign body may be the keratin of the horny
layer of the epidermis or hair. This happens in case of
epidermal cysts or due to penetration of hairs into the
dermis (barbers). Finally, keratin in the dermis may
occur in case of rupture of a hair follicle within the
dermis, for instance as a consequence of traumatic
pulling out of terminal hairs, which emerge from a
melanocytic nevus (Fig. 768, 769).
Granuloma
gluteale infantum
In spite of the clinical evidence
of its lesions, which are characterized by a tumor-like
appearance, the disorder was first reported in 1971. The
causal factors responsible for granuloma gluteale
infantum (GGI) have been not yet fully elucidated.
Candida albicans, halogens, diapers and topical
corticosteroids were suspected as causal factors. The
role played by Candida albicans is favored by positive
mycological findings. An exclusive role of Candida is
however unlikely, because mycological investigations are
not always positive in this disorder. Moreover, the
mycological investigations are often positive in this
site, even in case of seborrheic dermatitis and diaper
rash.
Finally, the tumor-like appearance of the lesions does
not favor a causal factor of Candida albicans. Such a
tumor-like appearance makes it very unlikely that its
lesions would have been unnoticed before their
description in 1971. Therefore it seems likely that the
precipitating cause or causes of these lesions have
appeared only in the last few decades. According to some
authors, the granulomatous lesions are caused by
topically applied fluorinated steroids. According to this
hypothesis granulomas are caused by fluorine.
Nevertheless, the granulomatous lesions improve
spontaneously, even when the steroid treatment is
continued.
Also diapers, introduced for general use 45 years ago,
play an important role in the etiopathogenesis of
granulomatous lesions. Lesions are always localized to
the area covered by the diapers and sometimes develop at
the point of maximum contact with them.
However, the most important role is played by the
corticosteroid creams, which first appeared a short time
before the appearance of this new clinical disorder.
In fact, almost all the cases reported in the relevant
literature have been treated with a corticosteroid cream.
The pathogenetic mechanism is not known but it is
possible that the lesions develop in the same way as
striae distensae from topical steroid therapy. Striae
distensae may at the onset be raised, reddish blue and
wheal-like. On the other hand, the lesions of granuloma
gluteale infantum often leave atrophic lax scars.
Finally, given the rarity of the disorder as compared
with the large diffusion of the causative factors, it is
likely that diathesic factors play a predisposing role.
From a clinical point of view, GGI clearly prevails in
males and always develops in children wearing diapers,
usually between the fourth and ninth month of age. The
disorder is always preceded by diaper rash (Fig. 770),
seborrheic or atopic dermatitis of the diaper area. There
is no correlation between the severity of the
pre-existing dermatitis and the development of the
granuloma. In fact, the granulomatous lesions often
develop while the dermatitis is improving.
The lesions tend to
be uniform in appearance and consist of reddish-blue
nodules (Fig. 771, 772), often elongated and parallel to
skin creases. The nodules spare the depth of the folds
and tend to develop at points of maximum contact with
diapers. Once the lesions have developed, they persist
for 3-6 weeks. Then they regress spontaneously over a
period of 2-4 weeks, sometimes leaving atrophic lax scars
(Fig. 773). Diaper rash can relapse but the granulomatous
lesions do not relapse, even if the use of fluorinated
steroids is continued.
The treatment of GGI
essentially consists in reassuring the family about the
benign course of the disorder and its spontaneous
regression in a few weeks.
Granuloma
annulare
Granuloma annulare is a chronic
granulomatous disorder. It is clinically characterized by
centrifugally extending granulomatous lesions and, on
light microscopy, by areas of focal degeneration of
collagen, which are surrounded by a reactive inflammatory
infiltrate.
Granuloma annulare is due to a peculiar cutaneous
reactivity, probably autoimmune in type, against multiple
and frequent allergenic stimuli. The hypothesis of an
autoimmune predisposition is essentially based on the
similarity of the pathological findings between granuloma
annulare and rheumatoid nodules and on the association
between granuloma annulare and insulin-dependent
diabetes.
From a clinical point of view, granuloma annulare mainly
affects children, after the first years of life, and
adolescents, although the disease has been observed even
in the old age.
The localized variant is the most frequent form of
granuloma annulare. It mainly affects the dorsal aspect
of the foot (Fig. 776), the dorsal aspect of the hand and
fingers (Fig. 774), legs, forearm and ear (Fig. 777). Its
asymptomatic lesions are usually distributed
asymmetrically, few in number, usually less than five,
and sometimes single.
The initial lesion
is a dermal, scarcely inflammatory papule, which extends
centrifugally, covering several millimeters a week. While
slowly extending centrifugally, the initial lesion
regresses at the center. This is why a few weeks after
the onset of the lesion, a characteristic ring (Fig. 774,
776) can be observed. The ring is visible and even better
perceptible at palpation.
At inspection, an annular relief, more or less evident,
is visible at the periphery, whereas in the center the
skin, which is underleveled as compared with the
peripheral ring, is normally colored or violaceous or
leaden.
At palpation, starting from the center towards the
periphery, we go up on the peripheral, infiltrated, firm,
non painful ring. Then we go down towards the central
skin, where granuloma already regressed.
There is no erythema on the peripheral ring neither on
the central skin. Moreover, there are no signs of
epidermis involvement, such as scaling, crusts or
exudation. The shape of the peripheral ring is roundish
or oval, rarely polycyclic due to the confluence of
several initial lesions. The peripheral ring is usually
continuous, although it can consist of close but non
confluent papules.
As for all the centrifugal lesions, the time of
appearance of the single lesions is related to their
diameter, namely the larger the lesion the earlier its
onset.
When not treated, lesions of granuloma annulare tend to
extend gradually for months or years till to a diameter
of more than 10 centimeters and then regress
spontaneously without any residua. Characteristically,
the lesions of granuloma annulare can suddenly regress as
a consequence of a biopsy or treatment.
However, the lesions almost always recur on the same site
or on sites close to the previous ones, sometimes before
the complete regression of the latter. In the latter case
the secondary lesions may recur inside the pre-existing
ring, giving rise to concentric rings.
Granuloma annulare is rarely associated to
insulin-dependent diabetes. In fact, in most cases
laboratory examinations are within normal limits.
On light microscopy (Fig. 775), at low magnification the
epidermis is spared, whereas in the reticular dermis
there are desertic areas surrounded by an inflammatory
palisade infiltrate, which is mainly composed of
histiocytes. The desertic areas are due to the partial
necrosis of the collagen. The latter is reminiscent of
the pathological findings of the rheumatoid nodule,
supporting the hypothesis of the autoimmune pathogenesis
of granuloma annulare.
The differential diagnosis from all the other roundish
dermatites is possible thanks to the lack of erythema and
alterations of the epidermis, in spite of the prominent
relief of the peripheral ring. The most difficult
differential diagnosis regards some variants of erythema
figuratum and especially lichen anulatus. The latter is
scarcely erythematous and its central area of healing may
be very similar in color to granuloma annulare. However,
its lesions are more superficial, sometimes covered by
mild scaling and finally differently distributed,
sometimes affecting some characteristic regions such as
the flexor aspect of the forearms.
The treatment of granuloma annulare is only symptomatic.
Therefore, it is justified only by esthetical reasons,
because the disorder does not bother the patient, who is
not exposed to further complications. This is why the
treatment is necessary when the disorder affects exposed
areas, such as the dorsal aspect of the hands. In the
latter case an occlusive treatment with corticosteroid
and tar ointments often leads to rapid, within 7-10 days,
regression of the cutaneous lesions.
Besides the localized form, other less frequent variants
are deep and generalized granuloma annulare. Deep
granuloma annulare may be isolated or associated to the
superficial localized form. It is characterized by
subcutaneous, asymptomatic nodules of difficult
diagnosis. The deep nodules are often misdiagnosed as
tumors and the right diagnosis is a pathological
surprise.
The generalized variant of granuloma annulare (Fig. 779)
is characterized by very numerous papules, often
distributed throughout the entire skin surface. The
possible presence of some larger papular lesions with
initial tendency to central resolution and thus with a
peripheral ring makes the diagnosis easier.
The linear and perforating form are other less frequent
forms of granuloma annulare.
Necrobiosis
lipoidica
Necrobiosis lipoidica is
histologically related with granuloma annulare, due to
the presence of focal degeneration and necrosis of the
collagen. The latter is more prominent in necrobiosis
lipoidica and sometimes associated to lipid deposits.
Moreover, the palisade inflammatory histiocytic
infiltrate is often associated with giant cells.
From an etiological point of view, necrobiosis lipoidica
is more closely related with diabetes or with a
prediabetic condition.
 Fig. 780
From a clinical point
of view necrobiosis lipoidica prevails in females, often
affecting with a few lesions the anterior surface of the
legs (Fig. 780).
Morphologically, its lesions are more inflammatory than
in granuloma annulare and often yellowish due to lipid
deposition. The central area is often atrophic and
characterized by superficial telangiectasic vessels.
Rheumatoid
nodules
Among the cutaneous signs of
rheumatoid arthritis there are rheumatoid nodules,
especially in the most severe forms. However, these
nodules may occur even in mild arthritis, precede the
articular localization and, finally, be independent of
joint localization.
Rheumatoid nodules are mainly localized on the hands,
knees, auricle, scapular region and occasionally other
sites, especially if subjected to pressure. The clinical
features are similar to those ones of deep granuloma
annulare, namely characterized by a firm, non painful
nodule (Fig. 781),
 Fig. 781
which can become spontaneously
painful when compressed between the bone and an external,
firm surface. On light microscopy, there is a focus of
complete collagen degeneration, which is surrounded by a
palisade histiocytic infiltrate.
Granuloma
faciale
The disorder, which affects the
face is characterized clinically by a chronic course and
histologically by a localized vasculitis with a massive,
dermal, polymorphonuclear and eosinophil infiltrate.
The etiology of granuloma faciale, which is not related
with systemic vasculitis, is not yet fully known.
It is rare in children, being more frequent in the young
adult.
 Fig. 783
From a clinical point of view, it
is characterized by an asymptomatic granuloma of the
face, red-brownish in color (Fig. 783), with clear-cut
borders. Mild scaling and superficial telangiectases can
be seen on its surface. With a magnifying glass dilated
follicular infundibula can also be seen. Its lesions can
be isolated or multiple.
On light microscopy, the disorder is characterized by a
massive infiltrate entirely occupying the dermis, though
sparing a thin area immediately under the epidermis. The
latter is always spared. The infiltrate mainly consists
of polymorphonuclear leukocytes and eosinophils, often
with findings of vasculitis. After an initial growth
phase, the lesion of granuloma faciale persist for a long
period of time.
Due to the long persistence and the scarce response to
the treatment, the disorder is associated with a main
esthetic significance.
Intralesional corticosteroids are the first choice
treatment. In case of a poor response to intralesional
corticosteroids, a surgical operation is indicated when
we are dealing with a single lesion. In some cases
covering cosmetics are indicated.
Sarcoidosis
Sarcoidosis is a disorder with a
wide clinical spectrum. It is characterized, from a
pathological point of view, by a granuloma mainly
consisting of epithelioid cells.
Its etiology has not been yet fully understood. Probably,
we are dealing with a particular reaction of the host
against different exogenous agents.
Whatever the affected organ may be, the histological
examination puts in evidence a lobular granuloma (Fig.
782), consisting almost exclusively of epithelioid cells,
sometimes associated with multinuclear giant cells.
Staining of reticular fibres shows a fine network
surrounding the granuloma and sometimes penetrating into
the latter. Asteroid bodies and lamellar concentric
structures, which are known as Schauman’s bodies,
may be present in the giant cells.
From a biological point of view, sarcoidosis is
characterized by a depression of cell immunity.
Tuberculinic anergy is the most typical expression of
such a depression.
Almost all the organs, included the skin, which is
involved in one fourth of cases, may be affected by
sarcoidosis. The cutaneous lesions may be various in
type, such as deep subcutaneous, nodular, papular,
plaque, angiolupoid (Fig. 784), chilblain lupus-like
lesions and erythema nodosum.
Sarcoidosis is rare in children. At this age the skin
involvement is characterized by papule, plaques and
erythema nodosum.
The prognosis of sarcoidosis is very variable and depends
on the affected organs and the different clinical course.
The diagnosis of sarcoidosis is made thanks to the
histological examination, the specific intradermal tests
(Kweim test), the anergy to tuberculin and, finally, the
increased levels of angiotensin converting enzyme (ACE).
When necessary, the treatment of sarcoidosis is
essentially based on the systemic steroids and, when the
skin is affected, on the topical corticosteroids.
Umbilical
granuloma of the newborn
Some days or weeks after the
elimination of the umbilical cord, a granulation tissue
may be sometimes observed in the umbilical region. The
granulation tissue is exuberant, reddish and not covered
by epidermis (Fig. 785). On light microscopy, a rich in
vessels granulation tissue is shown.
This granuloma can be treated with a silver nitrate
stick, after having protected with an inert ointment,
such as petrolatum, the surrounding healthy skin. One or
two applications of silver nitrate, with an interval of a
few days are usually enough.
The umbilical granuloma of the newborn should be
differentiated from talc granuloma, which is a foreign
body granuloma, and from polypoid lesions, which are
expression of embryonic residua, such as urachus and
vitelline duct.
Pyogenic
granuloma
Pyogenic granuloma and
telangiectatic granuloma are largely used synonymous.
Anyway, the pathological findings completely justify the
name of eruptive lobular angioma rather than the
synonymous names.
Eruptive angioma may occur at whatever age (Tab. 1).
However, it is more frequent in the child and adolescent.
According to many Authors, it may follow traumas, even
though traumatic stimuli are rarely reported in the
clinical history of these patients. The traumatic
hypothesis is supported by its localization on exposed
sites, such as the face, hands and lip. Sometimes an
eruptive angioma may occur on a viral skin proliferation,
such as molluscum contagiosum.
Eruptive angioma is a neoformation of endothelial cells.
The latter are characterized by a marked angiogenesis
giving raise to new capillaries. The proliferation of
endothelial cells is surrounded by a thinned epidermis,
which often penetrates beneath the neoformation, giving
raise to collarettes under its pedunculate basis (Fig.
789). The proliferation of endothelial cells may be
bilobated.
In most cases the neoformation is composed almost
exclusively by endothelial cells, with rare fibroblasts,
mastocytes and plasma cells. Many neutrophils appear when
the lesion undergoes erosion, due to its rapid growth.
The suppuration is anyway exceptional. Due to these
reasons, the name eruptive angioma should be preferred.
Eruptive angioma may occur in all the sites. However, the
most frequent site is the head, particularly the face
(Fig. 787, 788), which is followed by the upper trunk and
the hands.
The lesion is usually single. However, the removal of a
lobular eruptive angioma can be rarely followed by the
appearance of multiple satellite lesions (Fig. 786).
In most cases a red
spot first appears. The red spot rapidly grows, reaching
in a few week 2-3 mm in diameter. Due to the epidermal
collarette, the lesion is almost always pedunculate and
may be uni- or bi-lobated.
Due to its rapid growth, the thinned epidermis undergoes
erosion. Therefore, the lesion bleeds (Fig. 787),
frightening the parents and leading them to the
specialist.
Eruptive angioma may be then covered by a black crust or,
more rarely, may be eroded. If the lesion is not removed,
the proliferation reaches a maximum diameter of a few
millimeters and finally stops growing.
The stop of the growth usually coincides with the erosion
of the lesion even though this is not removed.
Pyogenic granuloma can be differentiated from other
angiomata thanks to its growth speed. The latter is
responsible for bleeding.
Hemangioma of the newborn and ruby angioma of the adult
are very different from a clinical point of view. They
grow slowly and rarely bleed. The raised angioma, which
complicates port-wine stain is more similar to pyogenic
granuloma and may bleed. However, it is not usually
pedunculated. Kaposi’s sarcoma usually arises on a
flat, red-wine patch and grows slowly.
In children eruptive angioma should be differentiated
especially from Spitz nevus. The latter is ten times less
frequent, grows more slowly (in months), is sessile, not
bilobated and with a smooth surface. Spitz nevus is
usually reddish as well as eruptive angioma. However, in
contrast with the latter, Spitz nevus gets brownish in
color when the blood is driven out of the superficial
telangiectases by digitopression. The brownish color is
due to the even scarce melanic pigment.
Pyogenic granuloma, especially when pedunculate, can be
easily removed by a "curette" under local
anesthesia. The bottom, especially in the center of the
peduncle, must be carefully scraped because the
proliferating vessels of eruptive angioma may in this
point go down into the dermis. Recurrences occur in less
than 10%. The appearance of satellite lesions may follow
or precede the surgical removal. The satellite lesions
are characterized by a minor tendency to grow and may
regress spontaneously.
E. Bonifazi
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