EUROPEAN JOURNAL OF PEDIATRIC DERMATOLOGY

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Eur. J. Pediat. Dermatol.                                                                        Contents vol. 9, 1999
Practical Pediatric Dermatology
9, T385-T400, 1999

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.

           
Fig. 758             Fig. 761

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.

           
Fig. 766             Fig. 767

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).

           
Fig. 768             Fig. 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.

           
Fig. 770             Fig. 771

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.

           
Fig. 772             Fig. 773

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.

           
Fig. 774             Fig. 775

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).

           
Fig. 786             Fig. 787

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

 

Dermatologia Pediatrica - Bari

e-mail: ejpd@teseo.it


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