Annulare and Pyogenic Granuloma

Granuloma annulare is a benign self-limited dermatosis characterized by a raised annular configuration. See the image below.

Pyogenic granuloma is misnamed, being neither pyogenic nor granuloma. It is a benign, acquired, vascular tumor of the skin and mucous membrane that appears as a rapidly growing vascular papule or nodule. Sometimes it appears at the site of a previous penetrating injury. Pyogenic granuloma is often observed in infancy and childhood but also may be observed in adults, particularly in pregnant women. See the image below.

Granuloma annulare may be localized, generalized, perforating, or subcutaneous. Lesions of the first 3 presentations have similar appearances, but each one follows a distinctive clinical course. Subcutaneous granuloma annulare appears differently, as it is a disease of childhood in which deep dermal or subcutaneous nodules lie on or near the periosteum and are distributed on the feet, lower legs, fingers, hands, forearms, scalp, and forehead.

Pyogenic granuloma is a disorder of angiogenesis whose underlying etiology remains unknown. A predilection exists for the head and neck, although lesions may appear on any part of the body. Purplish, pulpy, vascular lesions of pyogenic granuloma often involve the gum and other mucous membranes of the mouth.[1]

Granuloma annulare

Etiology of childhood granuloma annulare is unknown.

No good evidence supports suggestions that trauma, tuberculosis, streptococcal infection, herpes zoster/varicella, collagen vascular disorder, or diabetes mellitus are causally related to granuloma annulare. Recently, the first case report of granuloma annulare and diabetes mellitus has been described.[2] There are also weak associations with BCG vaccination; drugs such as allopurinol and zalcitabine; other viral infections such as EBV, HIV, hepatitis C, Parvovirus B19; autoimmune thyroiditis; and malignant conditions. Borrelia has also recently been implicated in one study.[3]

There is some evidence to suggest that granuloma annulare is an immunologic disease in the form of delayed type hypersensitivity reaction.

Pyogenic granuloma

The cause of pyogenic granuloma is unknown.

Suggested potential risk factors include pregnancy, birth control pills, bacterial and viral infections, microscopic arteriovenous anastomoses, and angiogenic growth factors, but no good evidence supports any of these as primary causative factors. In one large pediatric series, only 7% had any history of trauma preceding the development of the lesion.

Pyogenic granulomas have been reported arising within port wine stains. On rare occasions, lesions have been associated with malignancy.

Intraoral lesions can have an appearance and behavior very similar to the appearance and behavior of intraoral Kaposi sarcoma. These lesions may bleed extensively if biopsied; thus, HIV testing may be indicated when patients have intraoral lesions with the appearance of pyogenic granuloma.[4]

Pyogenic granuloma in pregnancy[5]

Pyogenic granuloma is common in pregnancy, with intraoral mucosal lesions appearing in 5% of pregnancies and in some unknown fraction of patients taking oral contraceptives.

Although the tumor mass often regresses after delivery or in response to adjustment of the contraceptive medication, spontaneous recurrences may be observed.

Etiology in pregnant women may be related to gingival inflammation, as the prevalence is reported to be less in patients with better oral hygiene.

Frequency

United States

Granuloma annulare is most common in children and young adults.

Solitary pyogenic granuloma is common and represents 0.5% of all skin nodules in children.

International

Pyogenic granuloma was 50% of reactive lesions compared to 21-26% reactive lesions in a local South Indian population between 1989-2009.[6]

Race

Granuloma annulare is believed to affect patients without respect to racial heritage.

Pyogenic granuloma may affect white populations more than other racial groups, but this is not well proven and the observation may reflect sampling bias.

Sex

Granuloma annulare has a slight tendency toward females. In granuloma annulare, females are slightly more affected than males.

In pyogenic granuloma, the male-to-female ratio is 3:2.

Age

More than two thirds of patients with granuloma annulare experience disease onset when younger than 30 years. In pediatric patients with granuloma annulare, the age of onset ranges from 1-14 years, with a mean of 4 years. The localized type of granuloma annulare occurs primarily in young children, whereas the generalized form is seen in patients younger than 10 years or older than 40 years.

Approximately one half of cases of pyogenic granuloma occur within the first 5 years of life.

Granuloma annulare

The prognosis of granuloma annulare is excellent, as the lesions usually regress spontaneously. Fifty to 70% with the localized type resolve after 1-2 years. The generalized type is less likely to resolve spontaneously. Granuloma annulare is a self-limited cosmetic disease without any systemic medical complications. On rare occasions, it may involve fascia and tendons and may cause sclerosis, lymphedema, and deformities such as joint ankylosis. Granuloma annulare has been epidemiologically linked to diabetes mellitus, necrobiosis lipoidica diabeticorum, and rheumatoid nodules.

Pyogenic granuloma

The prognosis of pyogenic granuloma is also excellent. Pyogenic granuloma is a benign vascular tumor, mostly occurring in childhood. Lesions may bleed and ulcerate.

Reassurance and referral are the principal and essential steps in patient education.

Granuloma annulare

History should focus on issues regarding diet, weight loss, and/or fever. This will help rule out other potential diagnoses such as trauma, infection, tumor, metabolic bone or skin disease, and inflammatory or autoimmune disease. In 2018, it was reported as an adverse effect of anti–programmed cell death-1 (PD-1) immunotherapy in a series of two patients.[7]

Children with granuloma annulare are usually otherwise healthy and have the lesions for several months without any other symptoms.

Pyogenic granuloma

In patients with suspected pyogenic granuloma, history should focus on the onset and associated symptoms of the rash.

Query the patient or parents regarding a preceding history of trauma, viral or bacterial infection, pregnancy, or HIV infection.

The patient and family should be questioned regarding prior rashes, port wine stain, and prior treatment.

The presence or absence of signs such as bleeding or ulceration should be noted.

Granuloma annulare

Children with granuloma annulare usually present with one or more firm, nontender soft tissue nodules on the extremities, scalp, or forehead.

Papules are 1-5 mm in diameter, flesh-colored or slightly pink, and smooth rather than scaly. They are easily distinguished from the lesions of erythema chronicum migrans, which are usually red in color and ring-shaped with central clearing.

Lesions may be generalized in children or in immunocompromised patients but are most often found along the extensor aspects of the extremities, in close proximity to joints.

Nodules of the scalp or forehead usually are fixed to periosteum and are only minimally mobile. Lesions of the extremities usually are fixed to fascia and are freely mobile.

Pyogenic granuloma

Physical examination should focus on the location and size of vascular papules, nodules, and peduncles that may be present on the skin or mucous membranes.

The presence or absence of bleeding or ulceration should be noted.

If present, other rashes should be described.

In cases of granuloma annulare without other etiology of the subcutaneous nodules, no complications are encountered.

The principal complication associated with pyogenic granuloma is hemorrhage, which can be significant and can require intervention.

Laboratory studies may be helpful if the diagnosis of granuloma annulare cannot be ruled out with a complete history emphasizing issues such as diet, weight loss, and/or fever. If an accurate history is unobtainable, a CBC count and erythrocyte sedimentation rate (ESR) should be obtained.

No laboratory studies are needed to make the diagnosis of pyogenic granuloma. CBC count, human chorionic gonadotropin (HCG), HIV, and biochemical profiles are needed only if there is concern for other etiologies.

Check blood glucose level if there is concern of diabetes mellitus and granuloma annulare.

Check rheumatoid factor if symptoms of rheumatoid arthritis are present.

Granuloma annulare

Radiographs are not necessary for diagnosis of granuloma annulare but may be helpful if other problems are suspected.

In granuloma annulare, the lesion is soft tissue mass without any calcification or bony involvement.

Pyogenic granuloma

Imaging studies are not useful in pyogenic granuloma.

Skin biopsy

To obtain a specimen, a 22- or 24-gauge needle may be gently passed tangentially just below the superficial capsular layer of the lesion, then flushed with saline to yield a small but adequate specimen.

Skin biopsy is diagnostic for granuloma annulare. Because the lesions regress, biopsy is needed only when a definitive diagnosis is required.

Skin biopsy is also diagnostic for pyogenic granuloma.

Granuloma annulare

Granuloma annulare rarely requires any treatment since spontaneous resolution is common.

Medical and surgical interventions should be avoided unless absolutely necessary.

Although there are numerous case reports of successful treatment of granuloma annulare, including medical and phototherapy options, randomized, controlled clinical trials are needed.[9]

Pyogenic granuloma

Patients with pyogenic granuloma may present with acute bleeding from the vascular lesions, particularly when they are intraoral. For patients who present with hemorrhage, bleeding often may be controlled with direct pressure and the airway should be secured if necessary. Intravenous access may be indicated if hemorrhage is severe..

A vasoconstrictor packing (eg, cocaine or tetracaine with adrenaline) sometimes may be needed.

When bleeding is refractory or recurrent, sclerotherapy by direct injection of 1-2 mL of 1% sodium tetradecyl sulfate into the vascular plexus is usually effective and may even provide a definitive cure.

Compress the lesion for 15 minutes following injection. Sclerotherapy usually is necessary in order to allow time for the tumor vessels to go into spasm.

Effective treatment includes excision (although this may be difficult if the lesion is extensive), electrodesiccation, curettage, chemical cauterization, and injection sclerotherapy. Carbon dioxide and argon lasers have been used successfully for superficial cases of pyogenic granuloma. Pulsed-dye laser also has been shown effective in the treatment of pyogenic granulomas when the lesion is superficial and of less than 0.5 cm thickness. Advantages of excision and electrocautery are ease of use and lack of recurrences according to one recent study in children.

A meta-analysis demonstrates that surgical excision offers the lowest overall recurrence rates (2.94%) and cryotherapy offered the lowest overall recurrence rate (1.62%).[10] If surgical excision and closure are not performed, cauterization with silver nitrate should be the first-line treatment.

In pediatrics, a case series has demonstrated the use of oral or topical beta-blockers to be a potential noninvasive treatment of mucosal pyogenic granulomas.[11]

If diagnosis is unproven, follow-up care with a dermatologist is indicated.

Further outpatient care is needed to follow the progress of lesions because as many as 20% of children with granuloma annulare experience recurrence.

Local recurrence after treatment of pyogenic granuloma by any method is not uncommon. In a one series, most of patients with uncomplicated pyogenic granuloma were treated with single shave excision and electrocautery, with no recurrences.[12]

Granuloma annulare

Medical treatments such as corticosteroids, potassium iodide, dapsone, niacinamide, chlorambucil, and isotretinoin have been tried, but none has been shown efficacious. Other treatments include liquid nitrogen cryotherapy, oral and topical PUVA photochemotherapy, UVA1 phototherapy, and cyclosporin. Isotretinoin should be reserved for patients with disseminated or refractory granuloma annulare because of potential serious toxicity.[13] Disseminated granuloma, which may be resistant to therapy, was responsive to low-dose fumaric acid esters in 63% of a series reported.[14] Moreover, adalimumab has been shown to be potentially promising to treat interstitial granuloma annulare.[15]

Class Summary

Corticosteroids are used for their potent anti-inflammatory activity.

Triamcinolone acetonide (Aristospan)

Triamcinolone acetonide treats inflammatory lesions that are responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.

Class Summary

Isotretinoin may have proliferative and inhibitory effects on collagen synthesis that may ameliorate symptoms associated with granuloma annulare.

Isotretinoin (Amnesteem, Claravis, Sotret)

Isotretinoin has been used as chemoprophylaxis of skin cancers.