Pyogenic Granuloma (Lobular Capillary Hemangioma)

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Background

Pyogenic granuloma (lobular capillary hemangioma) is a relatively common benign vascular lesion of the skin and mucosa whose exact cause remains to be determined.[1, 2] (See also Oral Pyogenic Granuloma.) The term pyogenic granuloma is actually a misnomer, in that these lesions are neither infectious nor granulomatous.

The lesion usually occurs in children and young adults as a solitary glistening red papule or nodule that is prone to bleeding and ulceration. Pyogenic granulomas typically evolve rapidly over a period of a few weeks, most often on the head, neck, extremities, and upper trunk.

Pyogenic granuloma often arises in pregnancy (or, rarely, with oral contraceptive usage), particularly on the gingiva or elsewhere in the oral mucosa,[3] and then is termed the pregnancy tumor.

Other pyogenic granuloma variants that have been well documented include the following subtypes:

Removal of pyogenic granuloma is indicated to alleviate any bleeding, discomfort, cosmetic distress, and diagnostic uncertainty. A number of malignant tumors may clinically mimic pyogenic granuloma, making histopathologic confirmation important if the presentation is atypical.

Aside from cutaneous and oral lesions, pyogenic granuloma has been reported throughout the gastrointestinal (GI) tract and the upper airway and at various ocular locations, as well as in the central nervous system (CNS), the bladder, and the internal vasculature. This article discusses only cutaneous and oral involvement.

Pathophysiology

The precise mechanism through which pyogenic granuloma develops has not been elucidated. Trauma, hormonal influences, certain medications, viruses, underlying microscopic arteriovenous malformations (AVMs), production of angiogenic growth factors, and cytogenetic abnormalities have all been postulated to play a role. Overexpression of transcription factors P-ATF2 and STAT3 also may play a role in tumorigenesis.[4]

Endothelial nitric oxide synthases (eNOS), CD34, and CD105/endoglin expression are markers of angiogenesis in pyogenic granulomas.[5, 6]  Tissue injury may trigger pathologic angiogenesis driven by FLT4, a tyrosine kinase receptor, and the nitric acid pathway.[7] COX-2 and interleukin (IL)-10 may be involved in the etiopathogenesis of oral pyogenic granulomas.[8]  BRAF and RAS mutations have been identified, suggesting a true neoplastic process.[9, 10]  Autophagy may play a part in the pathogenesis of pyogenic granuloma.[11]

Etiology

The cause of the typical pyogenic granuloma is not known. Trauma, hormonal influences, viruses,[12, 13] underlying microscopic AVMs, production of angiogenic factors, foreign bodies,[14]  and cytogenetic clonal deletion abnormalities[15] have all been implicated. Although trauma was long considered a primary cause of pyogenic granuloma, one large study found that only 7% of patients had a history of preceding trauma.[16]

Development of the lesions with the use of certain medications (retinoids, antiretrovirals, oncologic agents, and others) has been well documented (see History). A report by Al-Zahawi et al described a case of eruptive pyogenic granuloma occurring after COVID-19 vaccination.[17]  Another report by Maronese et al illustrated a case of eruptive pyogenic granuloma that presented 1 month after recovery from mild COVID-19.[18]

Epidemiology

United States and international statistics

Pyogenic granuloma is relatively common, representing 0.5% of all skin nodules in children.[16] The "pregnancy tumor" variant of pyogenic granuloma occurs in as many as 5% of pregnancies.[19]  The international frequency of pyogenic granuloma is likely similar to that in the United States.

Age-, sex-, and race-related demographics

Pyogenic granuloma is rare in children younger than 6 months. The peak age of onset for cutaneous lesions is the second decade of life.[20] For patients younger than 17 years, the mean age of presentation has been reported as 6.7 years.[16] With the exception of lesions occurring in pregnancy, the frequency declines linearly with age in adulthood. (See also Pediatric Pyogenic Granuloma.)

Pyogenic granulomas are equally prevalent in male and female patients, though oral mucosal lesions are twice as common in females,[2] probably as a consequence of the pregnancy tumor phenomenon.[3, 20]

No racial predilection has been identified.

Prognosis

Although pyogenic granuloma is a benign lesion, discomfort and bleeding occasionally may be significant. In rare instances, bleeding may be severe enough to cause anemia.

Lesions that recur despite repeated excisions can be particularly problematic. Pyogenic granulomas can recur regardless of the therapeutic modality employed. In one case of a recurrent, intractable pyogenic granuloma, the culprit was a missed foreign body.[21] Of the surgical treatment options, full-thickness skin excision appears to yield the lowest chance of recurrence (2.94%).[22]  

Patient Education

If a traumatic provoking factor is clearly causing the pyogenic granuloma, it should be avoided. Patients should be instructed to avoid retinoids if their pyogenic granuloma can be attributed to such agents.

History

The common solitary pyogenic granuloma (lobular capillary hemangioma) grows rapidly to its maximum size over a period of a few weeks.

Patients with pyogenic granuloma may report a painless glistening red lesion that bleeds spontaneously or after irritation. A history of trauma, peripheral nerve injury, or (rarely) an underlying systemic inflammatory disease may be elicited.[23]

The head, neck, digits, and upper trunk are affected most commonly.

There have been reports of lesions developing in a preexisting nevus flammeus or spider angioma, with the former instance noted to have occurred during pregnancy.[24] Pyogenic granuloma has also been reported after pulsed-dye laser treatment of both cherry angiomas and port-wine stains.[25, 26, 27]

Systemic retinoids may occasionally trigger pyogenic granuloma–like lesions. These occurred more frequently just after the approval of isotretinoin. Subsequently, a lower initial dose came to be favored, and this phenomenon became less common. Pyogenic granulomas have also been reported to occur with the use of acitretin[28] and even topical retinoids.[29]

Antiretroviral agents have been associated with the development of pyogenic granulomas, predominantly of the great toes.[30]

Periungual pyogenic granulomas occurring during epidermal growth factor receptor (EGFR) inhibitor therapy are a mounting problem for oncology patients, commonly arising after 2 months of drug exposure. Nailfold paronychia and pyogenic granuloma changes occur in as many as 24% of patients receiving panitumumab.[31]  Periungual pyogenic granulomas have also been found to be caused by ibrutinib (a tyrosine kinase inhibitor) therapy.[32] Other antineoplastic agents associated with pyogenic granuloma development include the following:

In addition, pyogenic granulomas have occurred with the use of the following:

The pregnancy tumor variant most often occurs in the second or third trimester. Cases arising with the use of oral contraceptives and hormone replacement therapy have been reported.[52]  

Rare multiple pyogenic granuloma lesions may be grouped or eruptive and disseminated in nature.[53] Congenital disseminated pyogenic granulomas have been reported.[54]  Eruptive disseminated pyogenic granulomas have developed after a drug hypersensitivity reaction[55] and after burn injuries, including those caused by a lightning strike.[56]  Disseminated pyogenic granulomas can also occur after isotretinoin use and granulocyte colony-stimulating factor (G-CSF) in immunodeficient patients.[27]

Adolescents and young adults are more prone to develop multiple recurrent satellite lesions after previous attempts at removal, especially on the trunk.

Untreated pyogenic granulomas eventually atrophy, become fibromatous, and slowly regress.

Physical Examination

The typical solitary pyogenic granuloma lesion is a bright-red friable polypoid papule or nodule that may range in size from a few millimeters to several centimeters. The average size is 6.5 mm,[16] , though a 25-cm giant pyogenic granuloma has been reported at the site of a scar in an HIV-positive patient.[57] The classic exophytic raspberrylike lesion has a moist surface and an epithelial collarette at the base. Bleeding, erosion, ulceration, purulence, and crusting are frequently noted. Regressing lesions appear as a soft fibroma.

Pyogenic granuloma has a predilection for the head and neck (see the first and second images below), the trunk, and the distal extremities (especially the fingers; see the third image below), but lesions may occur anywhere on the integument, including the genitalia.[58] Oral lesions are most common on the gingiva, lips, and tongue.[20]  



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Pyogenic granuloma on neck of young girl. Image from Jeffrey P Callen, MD.



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Multiple recurrent pyogenic granulomas on neck of young girl. Image from Jeffrey P Callen, MD.



View Image

Pyogenic granuloma on hand. Image from Jeffrey P Callen, MD.

The pregnancy tumor variant of pyogenic granuloma is most frequently found along the maxillary intraoral mucosal surface, but any intraoral, perioral, or nonoral tissue may be involved. One study reported an intranasal pyogenic granuloma associated with pregnancy and nasal piercings.[59]  

Pyogenic granuloma with satellitosis,[60] a subcutaneous subtype,[61] a linear presentation,[62] and a disseminated variant[53] have been described. The majority of satellites occur on the trunk, often around the scapula. The subcutaneous subtype of pyogenic granuloma is commonly found on the upper extremity.

A rare intravenous pyogenic granuloma variant[63] may present as a vascular polyp on the neck or upper extremities.

Imaging Studies

Ultrasonographic (US) features of digital subcutaneous pyogenic granulomas have been described.[67]  Kikusawa et al described US and computed tomography (CT) findings in subcutaneous pyogenic granuloma.[68]  In a review by Gonzalez et al, pyogenic granulomas were described as being "well-defined, exophytic, or polypoid epidermal and dermal hypoechoic structures" on US, with smooth margins and hypervascularity on Doppler studies with normal arterial flow.[69]

Procedures

Dermoscopy (dermatoscopy) patterns for pyogenic granuloma have been described.[70] A dermoscopic rainbow pattern has been reported.[71] Even dermoscopically, pyogenic granulomas may be indistinguishable from malignant melanoma.[72]

Reflectance confocal microscopic (RCM) findings of solitary red nodules, including pyogenic granuloma, have been published.[73]

A specimen for histologic examination may be obtained by means shave, punch, scalpel, or laser excision.

Histologic Findings

Histopathologic findings are similar for all variants of pyogenic granuloma. Early lesions resemble granulation tissue (numerous capillaries and venules with plump endothelial cells arrayed radially toward the skin surface amid an edematous stroma containing a mixed inflammatory infiltrate). Often, overlying erosive or ulcerative changes are noted. The matured polypoid lesion exhibits a fibromyxoid stroma separating the lesion into lobules. Reepithelialization of the surface and a peripheral hyperplastic adnexal epithelioid collarette may be noted, and less inflammatory infiltrate is present. A regressing pyogenic granuloma displays extensive fibrosis.

Extramedullary hematopoiesis is seen histologically in 10% of pyogenic granulomas.[74] Wilms tumor 1 protein expression is positive in vascular proliferations such as pyogenic granuloma.[75] Endothelial GLUT1 immunohistochemical expression is positive in infantile hemangioma but negative in pyogenic granuloma.[76]

The intravenous variant has less lobulation and is connected to the wall of a vein by a stalk.

Medical Care

If a clear provoking traumatic factor exists for the development of the pyogenic granuloma (lobular capillary hemangioma), it should be removed. When pyogenic granuloma can be attributed to use of medications, it may regress once the causative agent is withdrawn. Guidelines for the prevention and treatment of epidermal growth factor receptor (EGFR) inhibitor–related lesions have been published.[77]

Topical and systemic beta-adrenergic receptor antagonists have successfully treated cutaneous and mucosal pyogenic granulomas.[78, 79, 80, 81, 82, 17, 27]  Topical brimonidine eye drops have been to shown to be an effective treatment of cutaneous pyogenic granulomas.[83]

Topical imiquimod cream,[84] alitretinoin gel,[85]  and ingenol mebutate[86]  have been successfully used to treat pyogenic granulomas. In a case report, oral valacyclovir resolved a giant lesion showing herpes simplex virus (HSV)-1 antigens by immunohistochemistry in 2 weeks.[12] A report from Turkey described a patient with multiple pyogenic granulomas who showed clear improvement with oral erythromycin.[87]

Simple table salt,[88, 89] injectable sclerosing agents,[90, 91, 92] chemical cauterization with silver nitrate,[93] topical phenol for periungual lesions,[94] and photodynamic therapy with 5-aminolevulinic acid intralesional injection[95] have all been used.

Pyogenic granulomas with satellitosis that recurred after surgical excision have responded to intralesional[96] and systemic[97] steroids.

A recurrent giant pyogenic granuloma on the palm was successfully treated with intralesional bleomycin.[98]

One case reported using antibiotic therapy (ciprofloxacin 500 mg q12hr for 2 weeks) to treat an inflamed pyogenic granuloma that tested positive for Pseudomonas aeruginosa; this resulted in complete resolution and no recurrence of the benign lesion.[99]

Surgical Care

Shave, punch, or scalpel excision may be curative if the lesion is completely removed, and it provides a tissue specimen for pathologic confirmation of the diagnosis. Histologic evaluation is vital for any nonhealing lesion.[66]

Curettage and electrodesiccation are often successful, either individually or in combination, and may be performed after shave removal.[100, 101] Of the surgical options, full-thickness excision has the lowest rate of recurrence (2.94%).[22]  For large or difficult surgical areas, transarterial embolization may be an option.[102]  For digital pyogenic granulomas, a trap technique using a Penrose drain helps minimize bleeding.[103]

Various laser modalities have been successfully used.[104, 105, 106, 107, 108, 109]  Ligation of the lesion base[110] and cryosurgery[111]  have been reported to be effective for pyogenic granulomas.

Another treatment option for large pyogenic granulomas or ones that appear in sensitive locations is pressure therapy through the use of an elastic adhesive bandage over a piece of gauze. In one case report, 2 weeks of pressure therapy led to reductions in both the size and the vascularity of the lesion, and carbon dioxide laser therapy was used in conjunction to treat the remaining pyogenic granuloma.[112]

Many lesions occurring in pregnancy resolve with parturition; because recurrences are higher during pregnancy, some experts have recommended postponing removal until after delivery.[113]

Oral pyogenic granulomas may also be treated with a minimally invasive approach known as scaling and root planing, which can be done once a week for 4 weeks, in addition to adequate oral hygiene.[2]  

Long-Term Monitoring

The patient should seek follow-up care as early as possible if any evidence of recurrence of the pyogenic granuloma is present.

Timolol (Blocadren (DSC), Timol)

Clinical Context: 

Propranolol (Hemangeol, Inderal, Inderal LA)

Clinical Context: 

Ingenol mebutate topical (Picato)

Clinical Context: 

Imiquimod (Aldara, Zyclara)

Clinical Context: 

Alitretinoin topical (Panretin)

Clinical Context: 

Triamcinolone acetonide extended-release injectable suspension (Zilretta)

Clinical Context: 

Clobetasol (Clobex, Clobex Spray, Cormax)

Clinical Context: 

Brimonidine topical (Mirvaso)

Clinical Context: 

What is pyogenic granuloma (lobular capillary hemangioma)?What is the pathophysiology of pyogenic granuloma (lobular capillary hemangioma)?What causes pyogenic granuloma (lobular capillary hemangioma)?What is the global prevalence of pyogenic granuloma (lobular capillary hemangioma)?What are the racial predilections of pyogenic granuloma (lobular capillary hemangioma)?What are sexual predilections of pyogenic granuloma (lobular capillary hemangioma)?Which age groups have the highest prevalence of pyogenic granuloma (lobular capillary hemangioma)?What is the prognosis of pyogenic granuloma (lobular capillary hemangioma)?What is included in patient education about pyogenic granuloma (lobular capillary hemangioma)?Which clinical history findings are characteristic of pyogenic granuloma (lobular capillary hemangioma)?What medications may trigger pyogenic granuloma (lobular capillary hemangioma)?Which physical findings are characteristic of pyogenic granuloma (lobular capillary hemangioma)?Which conditions should be included in the differential diagnoses of pyogenic granuloma (lobular capillary hemangioma)?What are the differential diagnoses for Pyogenic Granuloma (Lobular Capillary Hemangioma)?What is the role of sonography in the workup of pyogenic granuloma (lobular capillary hemangioma)?What is the role of dermoscopy in the diagnosis of pyogenic granuloma (lobular capillary hemangioma)?How are specimens obtained for histologic evaluation of pyogenic granuloma (lobular capillary hemangioma)?Which histologic findings are characteristic of pyogenic granuloma (lobular capillary hemangioma)?How is pyogenic granuloma (lobular capillary hemangioma) treated?What is the role of surgery in the treatment of pyogenic granuloma (lobular capillary hemangioma)?When is long-term monitoring indicated in the treatment of pyogenic granuloma (lobular capillary hemangioma)?

Author

Joseph C Pierson, MD, Dermatology Residency Program Director, University of Vermont College of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Natasha Salmen, BS, Medical Student, Northeast Ohio Medical University College of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

Christine C Tam, MD, Managing Member, Certified Dermatologists

Disclosure: Nothing to disclose.

Donald Belsito, MD, Professor of Clinical Dermatology, Department of Dermatology, Columbia University Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Diane Pierson, DO, to the development and writing of this article.

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Pyogenic granuloma on neck of young girl. Image from Jeffrey P Callen, MD.

Multiple recurrent pyogenic granulomas on neck of young girl. Image from Jeffrey P Callen, MD.

Pyogenic granuloma on hand. Image from Jeffrey P Callen, MD.

Pyogenic granuloma on neck of young girl. Image from Jeffrey P Callen, MD.

Multiple recurrent pyogenic granulomas on neck of young girl. Image from Jeffrey P Callen, MD.

Pyogenic granuloma on hand. Image from Jeffrey P Callen, MD.