Background
Pyogenic granuloma (lobular capillary hemangioma[1] ) is a relatively common benign vascular lesion of the skin and mucosa whose exact cause is unknown. Also see the Medscape Drugs & Diseases article Oral Pyogenic Granuloma.
Pyogenic granulomas are misnamed; they 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, and then is termed the "pregnancy tumor."
Other pyogenic granuloma variants that have been well documented include the disseminated, subcutaneous, intravenous, and medication-induced (for example, retinoid, antiretroviral, and oncologic agent) 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 tract and upper airway, at various ocular locations, the central nervous system, the bladder, and the internal vasculature. This article discusses only cutaneous and oral involvement.
Pathophysiology
The precise mechanism for the development of pyogenic granuloma (lobular capillary hemangioma) is unknown. Trauma, hormonal influences, certain medications, viruses, underlying microscopic arteriovenous malformations, the production of angiogenic growth factors, and cytogenetic abnormalities have all been postulated to play a role. The overexpression of transcription factors P-ATF2 and STAT3 also may play a role in tumorigenesis.[2] Endothelial nitric oxide synthases (eNOS), CD34, and CD105/endoglin expression are markers of angiogenesis in pyogenic granulomas.[3, 4] . Tissue injury may trigger pathologic angiogenesis driven by FLT4, a tyrosine-kinase receptor, and the nitric acid pathway.[5] COX-2 and IL-10 may be involved in the etiopathogenesis of oral pyogenic granulomas.[6] BRAF and RAS mutations have been identified, suggesting a true neoplastic process.[7, 8]
Etiology
The cause of the typical pyogenic granuloma (lobular capillary hemangioma) is not known. Trauma, hormonal influences, viruses,[9, 10] underlying microscopic arteriovenous malformations, production of angiogenic factors, and cytogenetic clonal deletion abnormalities[11] have all been implicated. While trauma was long considered a primary cause, one large study found only 7% of patients had a history of preceding trauma.[12]
Development of the lesions with the use of certain medications (retinoids, antiretrovirals, oncologic agents, and others) has been well documented (see History for a complete list).
Epidemiology
Frequency
Pyogenic granuloma is relatively common, representing 0.5% of all skin nodules in children.[12] The pregnancy tumor variant of pyogenic granuloma occurs in up to 5% of pregnancies.[13] International frequency for pyogenic granuloma is likely similar to that of the United States.
Race
The frequency of pyogenic granuloma appears to be similar in all races.
Sex
Pyogenic granulomas are equally prevalent in male and female patients, though oral mucosal lesions are twice more common in females, likely due to the pregnancy tumor phenomenon.[14]
Age
Pyogenic granuloma is rare in children younger than 6 months. The peak age of onset for cutaneous lesions is the second decade of life.[14] For patients younger than 17 years, the mean age of presentation has been reported as 6.7 years.[12] Aside from those lesions occurring in pregnancy, the frequency declines linearly with age in adulthood. Also see the Medscape article, Pediatric Pyogenic Granuloma.
Prognosis
Pyogenic granuloma is a benign lesion; however, discomfort and bleeding occasionally may be significant. The latter may rarely be severe enough to cause anemia.[15]
Lesions that recur despite repeated excisions can be particularly problematic. Pyogenic granulomas can recur regardless of the therapeutic modality used. A missed foreign body was the culprit in one case of a recurrent, intractable pyogenic granuloma.[16] Among surgical options, full-thickness skin excision appears to yield the lowest chance of recurrence (2.94%).[17]
Patient Education
If a clear provoking traumatic factor is causing the pyogenic granuloma, it should be avoided. Instruct patients to avoid retinoids if their case 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 following irritation. A history of trauma, peripheral nerve injury, or rarely, an underlying systemic inflammatory disease may be elicited.[18]
The head, neck, digits, and upper trunk are affected most commonly.
Reports of lesions developing in a preexisting nevus flammeus or spider angioma exist, the former having been noted to occur during pregnancy.[19] Pyogenic granuloma has also been reported after pulsed-dye laser treatment of both cherry angiomas and port-wine stains.[20, 21]
Systemic retinoids may occasionally trigger pyogenic granuloma–like lesions.[22] These occurred more frequently just after the approval of isotretinoin. In current practice, a lower initial dose is used and this phenomenon is unusual. Reports have also described pyogenic granulomas occurring with the use of acitretin[23] and even topical retinoids.[24]
Antiretrovirals have been associated with the development of pyogenic granulomas, predominantly of the great toes.[25]
Periungal pyogenic granulomas occurring during epidermal growth factor receptor inhibitor therapy are a mounting problem for oncology patients, arising after 2 months of drug exposure. Nailfold paronychia and pyogenic granuloma changes occur in up to 24% of patients on panitumumab.[26]
Other antineoplastic agents associated with pyogenic granuloma development include the pyrimidine analog 5-fluorouracil,[27] its prodrug capecitabine,[28] mitoxantrone (an anthracenedione),[29] the taxanes docetaxel[30] and paclitaxel,[31] mTOR inhibitors,[32] and vemurafenib.[33]
In addition, pyogenic granulomas have occurred with the use of cyclosporine,[34] erythropoietin,[35, 36] levothyroxine,[37] anti-CD 20 monoclonal antibody therapy,[38] and following anti–tumor necrosis factor-alpha therapy.[39]
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.[40]
Rare multiple pyogenic granuloma lesions may be grouped or eruptive and disseminated in nature.[41] Congenital disseminated pyogenic granulomas have been reported.[42]
Eruptive disseminated pyogenic granulomas have developed following a drug hypersensitivity reaction[43] and after burn injuries, including lightning strike.[44]
Adolescents and young adults are more prone to develop multiple recurrent satellite lesions after prior attempts at removal, especially on the trunk.
Untreated pyogenic granulomas eventually atrophy, become fibromatous, and slowly regress.
Physical Examination
The typical solitary pyogenic granuloma (lobular capillary hemangioma) is a bright red, friable polypoid papule or nodule ranging from a few millimeters to several centimeters. The average size is 6.5 mm[12] , though a 25-cm giant pyogenic granuloma has been reported at the site of a scar in an HIV-positive patient.[45] The classic exophytic raspberrylike lesion has a moist surface and an epithelial collarette at the base. Bleeding, erosion, ulceration, purulence, and crusting frequently are noted. Regressing lesions appear as a soft fibroma.
The head and neck, trunk, and distal extremities (especially the fingers) are sites of predilection, but lesions occur anywhere on the integument, including the genitalia. Oral lesions are most common on the gingiva, lips, and tongue.[14]
Note the images below.
View Image | Pyogenic granuloma on the neck of the young girl. Courtesy of Jeffrey P. Callen, MD. |
View Image | Multiple recurrent pyogenic granulomas on the neck of a young girl. Courtesy of Jeffrey P. Callen, MD. |
View Image | Pyogenic granuloma on the hand. Courtesy of Jeffrey P. Callen, MD. |
The pregnancy tumor variant of pyogenic granuloma most frequently is found along the maxillary intraoral mucosal surface, but any intraoral, perioral, and nonoral tissue may be involved.
Pyogenic granuloma with satellitosis,[46] a subcutaneous subtype,[47] , and a disseminated variant[41] 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[48] may present as a vascular polyp on the neck or upper extremities.
Imaging Studies
Sonographic features of digital subcutaneous pyogenic granulomas have been described.[52] Subcutaneous pyogenic granuloma sonography and computed tomography findings have also been reported.[53]
Procedures
Dermoscopy patterns for pyogenic granuloma have been described.[54] However, even dermoscopically they may be indistinguishable from malignant melanoma.[55]
Reflectance confocal microscopic findings of solitary red nodules, including pyogenic granuloma, have been published.[56]
A specimen for histologic examination may be obtained by shave, punch, scalpel, or laser excision.
Histologic Findings
The histopathologic findings in all variants of pyogenic granuloma are similar. Early lesions resemble granulation tissue (numerous capillaries and venules with plump endothelial cells arrayed radially toward the skin surface amidst 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.[57] Wilms tumor 1 protein expression is positive in vascular proliferations such as pyogenic granuloma.[58] Endothelial GLUT1 immunohistochemical expression is positive in infantile hemangioma, but negative in pyogenic granuloma.[59]
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 pyogenic granuloma (lobular capillary hemangioma) development, remove it. Cases of pyogenic granuloma attributed to use of medications may regress upon withdrawal of the causative agent. Guidelines for the prevention and treatment epidermal growth factor receptor inhibitor–related lesions have been published.[60]
Topical and systemic beta-adrenergic receptor antagonists have successfully treated cutaneous and mucosal pyogenic granulomas.[61, 62]
Topical imiquimod cream[63] and alitretinoin gel[64] have both been successfully used to treat pyogenic granulomas. Oral valacyclovir resolved a giant lesion showing herpes simplex virus type–I antigens by immunohistochemistry in 2 weeks.[9] A report from Turkey described a patient with multiple pyogenic granulomas who showed clear improvement with oral erythromycin treatment.[65]
Injectable sclerosing agents,[66] chemical cauterization with silver nitrate,[67] topical phenol for periungual lesions,[68] and photodynamic therapy with 5-aminolevulinic acid intralesional injection[69] have all been used.
Pyogenic granulomas with satellitosis that recurred after surgical excision have responded to intralesional[70] and systemic[71] steroids.
A recurrent giant pyogenic granuloma on the palm was successfully treated with intralesional bleomycin.[72]
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.[51] Curettage and electrodesiccation is often successful, either alone, or in combination,[73] and may be performed after shave removal. Among surgical options, full-thickness excision has the lowest rate of recurrence (2.94%).[17] For large or difficult surgical areas, transarterial embolization may be an option.[74]
A variety of laser modalities have been successfully used.[75, 76, 77] Ligation of the lesion base[78] and cryosurgery[79] have been reported to be effective for pyogenic granulomas.
Many lesions occurring in pregnancy resolve with parturition; because recurrences are higher during pregnancy, some experts recommend postponing removal until after delivery.[80]
Long-Term Monitoring
The patient should seek follow-up care as early as possible if any evidence of recurrence of the pyogenic granuloma (lobular capillary hemangioma) is present.
Author
Joseph C Pierson, MD, Dermatology Residency Program Director, University of Vermont College of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Christine C Tam, MD, Managing Member, Certified Dermatologists
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, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine
Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.
Additional Contributors
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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