CLINICAL AND LABORATCRY INVESTIGATIONS Pediatric Dermatology Vol. 8 No. 4 Idl-lld
Pyogenic Granuloma (Lobular Capillary Hemangioma): A Clinicopathoiogic Study of 178 Cases Stephen J. Patrice, M.D., Karen Wiss, M.D., and John B. Mulliken, M.D. Division of Plastic Surgery and Division of Dermatology. The Children's Hospital. Harvard Medical School. Boston, Massachusetts
Abstract: Pyogenic granuloma (lobular capillary hemangioma) is a common acquired vascular lesion of the skin and mucous membranes in the pediatric age group. This is a retrospective analysis of 178 patients, 17 years of age and younger (mean age 6.7 yrs). Forty-two percent of the lesions occurred in the first five years of life; only 12% appeared in infants iess than 1 year old. The male:female ratio was 3:2. Most patients (74.2%) had no history of trauma or predisposing dermatologic condition. The mean lesional size was 6.5 mm and the mean duration at diagnosis was 3.8 months. The granulomas were most commonly located in the head and neck area (62.4%), followed in order of decreasing frequency by trunk (19.7%), upper extremity (12.9%), and lower extremity (5.0%). The preponderance (88.2%) occurred on the skin, the remaining ones involved the mucous membranes of the orai cavity and conjunctivae. Histoiogic examination demonstrated normal numbers of mast cells, in contrast to increased mast ceils characteristic of proliferative phase hemangiomas. Most lesions (n = 149) were treated by full-thickness skin excision and iinear closure; there were no recurrences in this group. The recurrence rate in 23 iesions treated by shave (intradermal) excision and cautery or cautery aione was 43.5%.
Pyogenic granuloma is a common vascular lesion of skin and mucous membranes in infancy and childhood. When seen early, it is a solitary, bright red papule. Primary eruption of multiple lesions or recurrent multiple granulomas after inadequate treatment are also well documented, although rare (1-16). The lesion grows rapidly, erupting through the skin, forming a stalk or pedicle. The majority are located in the head and neck area. Epidermal
breakdown, crusting, and bleeding usually initiate the first visit to a physician. The bleeding is episodic, copious, and often refractory to pressure, cautery, and caustics. Repeated visits to the emergency room for temporary control of bleeding are common. The child frequently has a blood-soaked adhesive bandage on the lesion; this prompted Thomson to label pyogenic granuloma "Band-Aid disease" (17) (Fig. I).
Address correspondence to John B. Mulliken. M.D.. Division of Plastic Surgery, Children's Hospital, 300 Longwood Avenue. Boston. MA 02115.
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sionally be confused with hemangioma. Both lesions unfortunately share the histoiogic designation capillary hemangioma. The differential diagnosis between pyogenic granuioma and the common hemangioma of infancy can usually be made with certainty based on history, physical examination, and evolution (17). Nevertheless, controversy persists as to whether pyogenic granuioma can be distinguished from hemangioma of infancy by light microscopy. Mills and co-workers histologicaily differentiated pyogenic granuioma from other benign vascular proliferative lesions and suggested the term lobular capillary hemangioma (32). Perhaps because it is such a banal lesion, it has rarely been the subject of investigation. This study was undertaken to analyze the clinical and histopathologic characteristics and the natural history of pyogenic granuioma in the pediatric age group. In addition, data on the efficacy of treatment were examined retrospectively. The term pyogenic granuioma (lobular capillary hemangioma) is used so as not to muddy further the nosologic water with another name. MATERIALS AND METHODS
Figure 1, A 14-month-old boy had episodic bleeding from a pyogenic granuioma of two months' duration. Note the adhesive on his cheek from many Band-Aid dressings. TABLE 1. Nomenclature of the Pyogenic Granuioma Name
Reference
Botryomycosis hominis Granuioma telangietodes Granuioma pediculatum benignum Granuioma telangiectaticum pediculatum Pseudobotryomycosis Granuioma telangiectaticum Granuioma pyogenicum Fibroangioma Hartzell disease Bloody wart Septic granuioma Hemangiomatous granuioma Lobular capillary hemangioma Eruptive capillary hemangioma
18 19 20 21 21 22-26 27.28 29 30 30 30 31 32 33
A jumbled nomenclature is responsible in part for misconceptions regarding etiopathogenesis {Table 1) (18-33). Pyogenic granuioma of the gingiva, occurring during pregnancy, is called epulis gravidanim or granuioma gravidarum (34-36). In the young pediatric age group., the disorder can occa-
This was a retrospective study of 206 infants and children with pyogenic granuioma registered in the Department of Pathology files. The inclusion criteria for cases culled over 45 years included a histopathologic diagnosis of pyogenic granuioma and sufficient clinical documentation by history, clinical features, and therapy. The histoiogic diagnosis was confirmed by review of the microscopic slides. Twenty-eight inflammatory lesions (granulation tissue), usually wound related, were excluded. The remaining 178 patients were reviewed, focusing on gross and histopathologic descriptions, operative reports, clinical history, and physical examination. The sex, race, and age of each patient were registered. Hypothetical factors of possible pathogenetic significance were recorded; I) preexisting capillary (portwine) stain, 2) dermatologic disorders such as eczematous dermatitis and psoriasis, 3) trauma, 4) viral infection, and 5) insect bite. The size, duration of symptoms, and history of bleeding, ulceration, or exfoliation was noted for each lesion. Exfoliation was defined as spontaneous necrosis and sloughing. The distribution of lesions was categorized according to anatomic location: head and neck, trunk, upper extremity, lower extremity, and perineum. Distribution was also determined according to type of
Patrice et al: Pyogenic Granuloma 269 epidermis, i.e. skin or mucous membrane (intraoral. intranasal, conjunctival, and tympanic membrane). The method of treatment was noted: cautery (chemical or thermal), laser, tangential excision and cautery, and excision and linear closure. Recurrent granulomas were grouped according to the particular unsuccessful treatment. Recurrence after spontaneous necrosis and exfoliation was also recorded. Data from four patients with many granulomas were separated from those on solitary lesions. The clinical data were analyzed for statistically significant relationships among the variables using the chi-square test of independence. Light Microscopy Hematoxylin and eosin-stained tissue for each of the 206 cases was available in the files. The slides were examined for the following histologic features: character of the endothelial and stromal elements, capillary lobule formation, inflammatory infiltrate, presence of an epidermal collarette, and epidermal ulceration. In addition, nine specimens were fixed in 10% buffered formalin, embedded in paraffin, cut and stained with safranin-0, and examined for mast cells (37). Forty high-power fields (450x) were counted for each of the specimens. The mean number of mast cells plus or minus standard deviation (SD) was calculated for each specimen.
and 17 (9.6%) were diagnosed between the first and the twelfth months of life. The frequency of granulomas declined almost linearly with age; only 4.5% occurred in the 15- to 17-year age group. Sex Of the 178 patients in the study, 107 (60.1%) were male and 71 (39.9%) were female, a ratio of 3:2. Predisposing Factors Table 2 shows the frequencies of various predisposing factors that may be associated with the pathogenesis of pyogenic granuloma. The majority of patients (74.2%) had no history of a preexistent cutaneous condition or trauma. Hypothetical predisposing factors, present in 25.8% of patients, included underlying capillary (port-wine) stain, followed by dermatologic disorders, trauma, localized viral infection, and insect bites. Figure 3 illustrates a pyogenic granuloma arising within a port-wine stain (dermal vascular malformation). Race Of the 135patientsfor whom race was reported, 113 were white. 18 were black, 2 were Hispanic, and 2 were Oriental. Caucasian patients comprised 83.7% of the study group and nonwhite groups accounted for 16.3%.
RESULTS
Lesion Size
Age The mean age of the patients was 6.7 years (SD = 4.9 yrs) and the range of ages was 16.8 years (Fig. 2). The majority of pyogenic granulomas (42.1%) appeared within the first five years of life. Only two infants (i.1%) manifested a lesion at birth. Three (1.7%) developed a lesion within the first month.
The size of the lesion was reported for 160 patients. The mean diameter was 6.5 mm (SD ^ 4.1). The range was 18 mm, with the smallest lesion being 2 and the largest 20 mm in diameter (Figs. 4 and 5). Duration Of the 137 patients for which the duration of lesions was reported, the majority were present one to
42. IK (75)
30.«
TABLE 2. Possible Predisposing Factors for Pyogenic Granuloma
(M) 23.OS (-11)
-1.5K IB)
Figure 2. Distribution of pyogenic granulomas according to age of onset. Most lesions appeared in the 0- to 5-year age group; however, 12.4% occurred before 12 months, and only 2.8% within the first month of life.
Condition
Number of Patients
None Port-wine stain Dermatologic disorder Trauma Viral infection Insect bite Totals
132 16 14 12 2 2 178
74.2 9.0
7.9
6.7 LI LI 100.0
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Figure 3. Pyogenic granuloma often occurs in an area of dermal capillary malformation {Left) A 12-year-old girl with port-wine stain of the left cheek (second division trigeminal nerve); note the tiny vascular spot within the stain. (Right) Two weeks later the pyogenic granuloma is florid.
= 7.2) and 2.0 months, respectively, and the range was 71.9 (minimum 5 days, maximum 6 yrs). Anatomic Location
Figure 4. A 1.5-year-old with two-month history of an oozing, crusted, pyogenic granuloma of the lower eyelid.
three months before treatment, regardless of anatomic location. The standard deviation for duration was greater than the mean because of outlying data points. Therefore, the median value was also calculated. The mean and median duration was 3.8 (SD
Two-thirds of pyogenic granulomas were located in the head and neck area, followed by trunk, upper extremity, and lower extremity (Fig. 6). Within the head and neck region, the most frequent sites were the cheek (28.8%), oral cavity (13.5%). scaip (10.8%), forehead (9.9%), and eyelid and lips (both 9.0%). In this study, 88.2% (n - 157) lesions occurred on skin and 11.8% (n ^ 21) on mucous membrane. One appeared on the mucous membrane of the nose and another on the tympanic membrane. Lesions of the posterior and anterior trunk occurred with approximately equal frequency. The majority of lesions of the upper extremity were on the shoulder (43.5%), followed by the hand and fingers (30.4%) and upper and lower arm (26.1%). Lesions of the lower extremity were located with similar frequency on the thigh, calf, foot, and toes.
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ANATOMIC DISTRIBUTION OF SOLITARY PYOGENIC GRANULOMA
%Lesions Conjunct ivo
Upptr Extremity-
Perineum-0
Lam-Extremity- SO
Figure 5. A 12-year-old boy with a four-month history of a tiny, 3-mm, pedunculated pyogenic lesion of the anterior neck. Bleeding and Ulceration
Bleeding occurred in 104 (64.2%) of 162 patietits. Ulceratioti was present in 61 (36.3%) of 168 patients. Treatment and Recurrence
None of the 149 lesions treated by surgical excision recurred. However, the recurrence rate was 43.5% for 23 lesions treated by tangential excision and cautery {n = 16) or cautery alone in = 7). Six lesions, all of which were located on the face, underwent necrosis and exfoliation; five recurred. No lesions were treated by laser in this series. Recurrence with multiple lesions occurred in four treated patients (ranging in age from 23 mo-6.5 yrs). These satellite lesions were 1 to 3 mm in diameter and were located at a distance of up to 5 cm away from the original granuloma. The majority of recurrent granulomas had been treated by cautery or tangential excision and cautery. They were
Figure 6. Anatomic distribution of solitary pyogenic granuloma in 178 patients. Two-thirds of lesions occurred in the head and neck region, particularly on the cheek.
small, and correlations between specific treatment modalities and recurrence, with or without satellite lesions, was not statistically significant. Four patients had multiple granulomas. ln three of them, the lesions occurred in pairs, were of equal size, and were located at a distance of 0.5 to 1 cm apart. The fourth patient, a 2-month-otd boy, was born with numerous granulomas ranging in size from 0.4 lo 4.0 cm in diameter and involving the head and neck, trunk, upper and lower extremities, and perianal area (Fig. 7). Histopathology
The typical low-power microscopic appearance of pyogenic granuloma was a well-circumscribed, exo-
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the deeper layer, particularly in lesions with an intact epidermis. With high-power magnification, the immatureappearing capillaries were lined with activeappearing, plump, endothelial cells. The vasoproUferative endothelium exhibited occasional mitotic figures; there was no pleomorphism or atypia. In the nine lesions studied, the mean number of mast cells per high-power field was 3.16 (SD = 2.33). DISCUSSION Clinical Features
Figure 7. Rare instance of large and small multiple pyogenic granulomas in a 2-month-old boy that were present at birth.
phytic mass attached to a narrow stalk, consisting of aggregates of proliferating capillaries located within an edematous matrix (Fig. 8). The epidermal surface often evidenced focal areas of atrophy or frank ulceration. usually present at the summit of the lesion. Several lesions were slightly undermined at the base by the inward growth of acanthotic epithelium, the so-called epithelial collarette. Different histopathologic patterns were seen in the superficial and deep components of these lesions. Immature capillaries with interspersed fibroblastic tissue (resembling granulation tissue) were present within the edematous stroma of the superficial lesion. However, the deeper portions consisted of proliferating masses of capillaries arranged in a distinctive iobular pattern. Some lobules extended into the deep dermis. The stroma of the deeper component was more dense and fibrous. Capillaries located in various levels of the dermis were poorly canalized. An infiltrate of lymphocytes and plasma cells was noted occasionally within the stroma of the superficial region but was usually absent from
Clinical characteristics are sufficient to distinguish pyogenic granuloma from other benign proliferative vascular lesions, particularly infantile hemangioma. Pyogenic granuloma begins as an erythematous macule that evolves into a papule. The lesion grows rapidly and frequently becomes pedunculated, or it may remain sessile. The integrity of the overlying epidermis determines the granuloma" s color and texture. With an intact epidermis, the lesion is bright red and smooth. When ulcerated it is covered by a dark, adherent crust or has a moist, granular surface (17). The majority of pyogenic granulomas manifested in children older than 1 year. In only two patients were solitary iesions, and in one patient multiple granulomas. present at birth. The mean diameter of pyogenic granulomas was 6.5 mm, with a range between 0.2 and 2 cm. Over 75% were less than 1 cm. A history of spontaneous ulceration and bleeding is commonplace; the latter occurred in two-thirds of patients in our study. The lesions were 1.5 times more common in males. Other investigators also reported a slight preponderance of males in patients under 18 years of age and an increased frequency in females between ages 18 and 39 years (32). The majority of granulomas occurred in white patients (83.6%); this reflects the racial distribution of patients seen in our institution. The lesions were present more commonly on the upper extremity than the lower extremity. Perhaps this anatomic distribution is related to the density of cutaneous vascularity; that is, greatest in head and neck followed by the trunk and extremities (38). Histologic Features
Review of the literature suggests that pyogenic granulomas can be distinguished from other acquired vascular lesions by microscopy, including
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Figure 8. Light microscopy of pyogenic granuioma. (Left) Low-power demonstrates the weii-circumscnoea mass of proliferating capillaries in an edematous matrix. Note the epithelial coUarette at the base, and the intact epidermis. (Hematoxylin & eosin; magnification 40x.) (Right) High-power photomicrograph of pyogenic granuioma demonstrates the capillary-size channels encased in myxoid to fibromyxoid stroma. (Hematoxylin & eosin; magnification 200 X.)
immunocytology, and by ultrastructural methods. Pyogenic granuioma characteristically exhibits a histologic lobular arrangement of capillaries within the deep portion of the lesion. Mills et ai (32) emphasized that these lobules are the critical identifying feature of the lesion, rather than the presence of an epithelial collarette, ulceration. inflammatory infiltrate, or edematous matrix. They proposed the term lobular capillary hemangioma to replace pyogenic granuioma (32). Mast cells have long been recognized as participants in angiogenic lesions, particularly neoplasms. We found normal levels in the nine specimens of pyogenic granuiomas that were stained for mast cells. This is in contrast to the markedly elevated number of mast celJs typically seen in proliferative phase hemangiomas (37). Immunohistochemical staining of the endothelial cells of pyogenic granuiomas with factor VIIIrelated antigen and ulex europeas agglutinin lectin was reported to be negative (39,40). The lesion
stains strongly for smooth muscle actin within the proliferating celiular element (41). This suggests that the pericyte is the major hyperplastic cellular component. This staining pattern may also help to differentiate pyogenic granuiomas from infant hemangiomas and borderline malignant vascular tumors such as epithelioid hemangioendothelioma of the oral cavity (42). Ultrastructural studies have shown that pyogenic granuiomas demonstrate connective tissue synthesis with significant production of giycosaminoglycan, fibroblasts and pericytes with well-developed rough endoplastic reticuium. and immature extracellular collagen fibers (43). Although endothelial nuclei may be elongated and lobulated, these cells appear to have normal structure and organelles., with little evidence of increased biosynthetic orcatabolic activity and relatively normal basement membranes (43). Ultrastructura! analysis of several granuiomas in our series demonstrated multiplica-
274 Pediatric Dermatology Vol. 8 No. 4 December 1991 tion of basal lamellae, as would be expected in lesions with increased endothelial turnover (44). Tufted angioma is a newly recognized, acquired, vasoproliferative lesion of childhood that is closely related to but clinically and histologically distinguishable from pyogenic granuloma (45,46). Tufted angioma grows slowly; it appears within the first five years of life but rarely before age 1 year. The usual location is the upper chest, neck, and shoulder, not the face or scalp. The lesions are plaquelike, dull red. macular or papular, and 2 to 5 cm in diameter. Microscopically, there are circumscribed lobules of hypertrophied capillaries within the mid to lower dermis. In contrast to pyogenic granuloma. the lobules contain closely packed endothelium with few dilated lumina, there is a mucin-rich stroma, and lymphatic-like channels are seen adjacent to and at a distance from the capillary tufts. Etiology The etiology of this lesion remains unknown. Several investigators hypothesized that it is a hyperproliferative vascular response to infective organisms of low virulence. The entity was first described in 1897 by Poncet and Dor, who believed thai the etiologic organisms were fungi (18). In the early nineteenth century, Crocker and Hartzel! applied the term granuloma pyogenicum. believing the lesion to be a localized bacterial infection (27.28). A viral etiology has also been suggested but has never been documented in case reports (4). Some authors suggest that the granuloma arises from trauma to the skin or mucous membrane, healing abnormally with excessive formation of granulation tissue (21). However, in our study only 7% of the patients gave a history of trauma preceding the onset of a lesion, and only 1.2% had a history of viral infection. Pyogenic granuloma can be categorized as a disorder of angiogenesis of unknown etiology. Its pathogenesis involves a neovascular response to an angiogenic stimulus, promoting predominant growth of pericytes with less effect on endothelial cells. The fact that it frequently occurs within a port-wine stain and has a predilection for the head and neck suggests that the unknown angiogenic stimulus is most likely to be triggered in dense or dilated vascular beds (47). Approximately 9% of the patients in this study had a history of the granuioma arising within a port-wine stain; an underlying dermatologic disorder, such as psoriasis and eczematous dermatitis, accounted for 7.6% of patients. Perhaps the increased infiammatory angiogenesis
associated with these conditions also stimulates pericytic hyperplasia. Endocrine factors have also been suggested as contributory to vascular proliferation in pyogenic granuloma (48). Treatment
We could not document the frequency with which pyogenic granuloma may exfoliate and never require treatment. All lesions in this study were removed by surgical excision, with the exception of a single one that underwent spontaneous necrosis and subsequent healing without recurrence. It is possible that some of these lesions could have regressed spontaneously at some future time, yet, mature granulomas tend lo persist. Lesions of long duration, ranging from 6 to 20 years, are reported (21). The usual treatment is cautery with silver nitrate, electrodesiccation. curettage, or tangential excision and cautery. In this retrospective study, the recurrence rate was 43.5% for 23 lesions treated by cautery alone (i.e., chemical or thermal) or after tangential excision and cautery. Curiously, four granulomas recurred with multiple satellite lesions. a rare phenomenon, previously documented (6-16). A recurrence rate of 16% is reported for intraoral lesions treated by superficial excision (49). However, only a prospective study would best document the effectiveness of primary curettage and/or cautery. In our study, no recurrences were seen after full-thickness excision and linear closure. Argon and pulsed dye lasers, which have been successful in the treatment of port-wine stain, have had equivocal results in the therapy of pyogenic granulomas. Vascular proliferatioti below the papillary dermis is beyond the range of argon laser, which only penetrates 1.0 to 1.5 mm beneath the epidermis. Results with the pulsed dye laser also have been disappointing. In theory, the neodymium:yttrium-argon-gamet laser should have sufficient penetration (4-6 mm) to destroy the lesion, however, scarring can be esthetically unacceptable with this modality. ACKNOWLEDGMENTS
The authors extend their gratitude to Richard A. LaBrie, Ed.D., for his statistical analysis of our data. We are indebted to Harry P. W. Kozakewich, M.D.. for his guidance in evaluating the histopathologic specimens, and to A. J. Man"ogi, M.D., for his contributions to the discussion of histopathology.
Patrice et al: Pyogenic Granuloma
REFERENCES 1. Frain-Bel! W. Mu!tiple pyogenic granulomata. Br J Dermatol 1958;70:428-429. 2. Juhlin L, Hjertquest S, Ponten J, Wallin J. Disseminated granuloma pyogenicum. Acta Dermatovenereol (Stockh) 1970;50:134-!36. 3. De Kaminsky AR. Otero AC. Kaminsky CA, Shaw M. Formentini E, Abulafia S. Multiple disseminated pyogenic granuloma. BrJ Dermatol 1978;98:46i-464. 4. Nappi O. Wick MR, Disseminated lobular capillary hemangioma {pyogenic granuloma): clinicopathologic study of two cases. Am J Dermatopathol 1986:8: 379-385. 5. Nodi F. Multiple sogennante telangiektatische granulome. Hautarzt 1980:31:471-477. 6. Allen RG. Rodman OG. Pyogenic granuloma recurrent with satellite lesions. J Dermatol Surg Oncol 1979:5:490-493, 7. Zaynoun ST. JuljuUan HH, Kurban AK. Pyogenic granuloma with multiple satellites. Arch Dermatol 1974:109:689-691. 8. Evans C. Pyogenic granuloma with local recurrences. BrJ Dermatol 1957:69:106-108. 9. Warner J. Wilson-Jones E. Pyogenic granuloma recurring with multiple satellites: a report of eleven cases. BrJ Dermatol 1968:80:218-227. 10. Coskey RJ. Mehregan AH. Granuloma pyogenicum with multiple satellite recurrences. Arch Dermatol l%7:96:71-73. 11. Center S. Granuloma pyogenicum: a case of multiple benign angiomata. Br J Dermatol 1959:61:130^131. 12. Fisher I. Recurrent multiple pyogenic granuloma with multiple satellites: features of Masson's hemangioma. Cutis 1977:20:201-205. 13. Nagashima N. Niizuma K. Multiple satellite granuloma teleangiectaticum. Jpn J Dermatol 1972:82:1-4. 14. Amerigo J. Gonzales-Campora R, Galera H. et al: Recurrent pyogenic granuloma with multiple satellites: clinicopathological and ultrastructural study. Dermatologica 1983:166:117-121, 15. Grupper CH. Pastel A. Granuloma pyogenique avec satellizations multip!e angiomateuses. Bull Soc Fr Dermatol Syph l969;76:496-497. 16. Wilson BB. Greer KE. Cooper PH. Eruptive disseminated lobular capillary hemangioma (pyogenic granuloma). J Am Acad Dermatol 1989:21:391-394. 17. Mulliken JB. Diagnosis and natural history of hemangiomas. In: Mulliken JB, Young A. eds. Vascular birthmarks: hemangiomas and malformations. Philadelphia: WB Saunders. 1988.41-62. 18. Poncet A, Dor L. Botryomycose humaine. Rev Chir 1897:18:996-1003. 19. Kiittner H. Ueber telangiektatische Granulome. Beitr Z Klin Chir 1905:47:1-36. 20. Frederic J. Ueber die sogennante menschliche Botryomykose. Dtsch Med Wochenschr 1904:30:549-587. 21. Kerr DA. Granuloma pyogenicum. Oral Surg 1951:4: 158-176. 22. Schwenzer N. Das Granuloma Teleangiectaticum
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unter Bezugnahme auf einen Fall in Mundhohle. Zahnarzti Reform 1955:56:251. 23. Mathis H. Ober das Granuloma Teleangiectaticum der Inhaltsgebilde der Mundhohle. Dtsch Zahnarztl Z 1957:12:23-28. 24. Janczuk Z. Sladka H. Przypadek Ziaminiaka Jezyka Pochodzenia Naczyniowego (granuloma teleangiectaticum). Czas Stomat 196O;I3:631. 25. Peripopoulos G. Teleangiectatic granulomata of the gingiva. Acta Stomato! Hellenica 1961;5:201. 26. Knak G, Ober das Vorkommen des Granuloma Teleangiectaticum im Bereich der Mundhohle. Schweiz Med Zahnheilk l%6:76:492-509. 27. Crocker HR. Diseases of the skin. Philadelphia: P Blakiston's Son. 1903:1^146, 28. Hartzell MB. Granuloma pyogenicum (botryomyco sis of French authors). J Cutan Dis Syph I9O4;22: 520-525. 29. Martens VE. MacPherson DJ. Fibroangioma, granuloma gravidarum. juvenile angiofibroma and urethral caruncle. Arch Patho! 1956.61:120-^124. 30. Ronchese F. Granuloma pyogenicum. Am J Surg 1965:109:430-431. 31. Angelopoulos AP. Pyogenic granuloma of the oral cavity: statistical analysis of its clinical features. J Oral Surg 1971:29:840-847. 32. Mills SE. Cooper PH. Fechner RE. Lobular capillary hemangioma: the underlying lesion of pyogenic granuloma. Am J Surg Palhol 1980:4:471^79. 33. Marsch W. Zur Ultrastruktur des eruptiven kapillaren hamangioms (Granuloma pyogenicum sive leleangiectaticum). Hautarzt 1984:35:92-%. 34. Tiilila I. Epulis gravidarum. Suom Hammaslaak Toim 1962;58(suppl 1):9. 35. Ziskin DE. Blackberg SN. Stout AP. The gingivae during pregnancy. Surg Gyneco! Obstet 1933;57:719726. 36. Weir JC. Silberman SL. Cohen LA. Recurring oral pregnancy tumors. Obstet Gynecol 1979:54:358-360. 37. Glowacki J. Mulliken JB. Mast cells in hemangiomas and vascular malformations. Pediatrics 1982:70: 48-51. 38. Pasyk VA. Thomas SV. Hassett CA. et al. Regional differences in capillary density of the normal human dermis. Plast Reconstr Surg 1989:83:939-945. 39. Sehested M, Hou-Jensen K. Eactor Vlll-related antigen as an endothelial cell marker in benign and malignant diseases. Virchows Arch [A] 1981:391:217225, 40. Burgdorf WHC. Mukai K, Rosai J. Immunohistochemicai identification of factor Vlll-related antigen in endothelial cells of cutaneous lesions of alleged vascular nature. Am J Clin Pathol 1981;75:167-171. 41. Mukai K. Schollmeyer JV. Rosai J. Immunohistochemicai localization of actin: applications in surgical patho!ogy. Am J Surg Pathol 1981.5:91-97. 42. Marrogi AJ, Boyd D. El-Mofty SK. Waldron C. Epithelioid hemangioendothelioma of the oral cavity: report of two cases and review of the literature. J Oral Maxi!lofacia! Surg 1991:49:633-638. 43. Davies MG. Barton SP, Atai F, Marks R. The abnor-
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mal dermis in pyogenic granuioma: histochemicat and ultrastructural observations. J Am Acad Dermatol 1980;2:132-142. 44. Vrako R. Basal lamina scaffold—anatomy and significance for maintenance of orderly tissue structure: A review. Am J Surg Pathol 1974;77:313-346. 45. Padilla RS, Orkin M, Rosai J. Acquired "tufted" angioma (progressive capillary hemangioma): a distinctive clinicopathologic entity related to lobular capillary hemangioma. Am J Dermatopathol 1987;9: 292-300. 46. Wilson JE, Orkin M. Tufted angioma (angioblas-
toma): a benign progressive angioma. not to be confused with Kaposi's sarcoma or low-grade angiosarcoma. J Am Acad Dermatol 1989;20:214-225. 47. Swerlick RA. Cooper PH. Pyogenic granuioma (lobular capillary hemangioma) within port-wine stains. J Am Acad Dermatol 1983;8:627-630. 48. Leyden J. Master G. Oral cavity pyogenic granuioma. Arch Dermato! 1973;lQ8:226-228. 49. Bhaskar SN. Jacoway JR. Pyogenic granuioma: clinical features, incidence, history, and result of treatment: report of 242 cases. J Oral Surg 1966:24:391398.
Pyogenic Granuloma (Lobular Capillary Hemangioma): A Clinicopathoiogic Study of 178 Cases Stephen J. Patrice, M.D., Karen Wiss, M.D., and John B. Mulliken, M.D. Division of Plastic Surgery and Division of Dermatology. The Children's Hospital. Harvard Medical School. Boston, Massachusetts
Abstract: Pyogenic granuloma (lobular capillary hemangioma) is a common acquired vascular lesion of the skin and mucous membranes in the pediatric age group. This is a retrospective analysis of 178 patients, 17 years of age and younger (mean age 6.7 yrs). Forty-two percent of the lesions occurred in the first five years of life; only 12% appeared in infants iess than 1 year old. The male:female ratio was 3:2. Most patients (74.2%) had no history of trauma or predisposing dermatologic condition. The mean lesional size was 6.5 mm and the mean duration at diagnosis was 3.8 months. The granulomas were most commonly located in the head and neck area (62.4%), followed in order of decreasing frequency by trunk (19.7%), upper extremity (12.9%), and lower extremity (5.0%). The preponderance (88.2%) occurred on the skin, the remaining ones involved the mucous membranes of the orai cavity and conjunctivae. Histoiogic examination demonstrated normal numbers of mast cells, in contrast to increased mast ceils characteristic of proliferative phase hemangiomas. Most lesions (n = 149) were treated by full-thickness skin excision and iinear closure; there were no recurrences in this group. The recurrence rate in 23 iesions treated by shave (intradermal) excision and cautery or cautery aione was 43.5%.
Pyogenic granuloma is a common vascular lesion of skin and mucous membranes in infancy and childhood. When seen early, it is a solitary, bright red papule. Primary eruption of multiple lesions or recurrent multiple granulomas after inadequate treatment are also well documented, although rare (1-16). The lesion grows rapidly, erupting through the skin, forming a stalk or pedicle. The majority are located in the head and neck area. Epidermal
breakdown, crusting, and bleeding usually initiate the first visit to a physician. The bleeding is episodic, copious, and often refractory to pressure, cautery, and caustics. Repeated visits to the emergency room for temporary control of bleeding are common. The child frequently has a blood-soaked adhesive bandage on the lesion; this prompted Thomson to label pyogenic granuloma "Band-Aid disease" (17) (Fig. I).
Address correspondence to John B. Mulliken. M.D.. Division of Plastic Surgery, Children's Hospital, 300 Longwood Avenue. Boston. MA 02115.
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sionally be confused with hemangioma. Both lesions unfortunately share the histoiogic designation capillary hemangioma. The differential diagnosis between pyogenic granuioma and the common hemangioma of infancy can usually be made with certainty based on history, physical examination, and evolution (17). Nevertheless, controversy persists as to whether pyogenic granuioma can be distinguished from hemangioma of infancy by light microscopy. Mills and co-workers histologicaily differentiated pyogenic granuioma from other benign vascular proliferative lesions and suggested the term lobular capillary hemangioma (32). Perhaps because it is such a banal lesion, it has rarely been the subject of investigation. This study was undertaken to analyze the clinical and histopathologic characteristics and the natural history of pyogenic granuioma in the pediatric age group. In addition, data on the efficacy of treatment were examined retrospectively. The term pyogenic granuioma (lobular capillary hemangioma) is used so as not to muddy further the nosologic water with another name. MATERIALS AND METHODS
Figure 1, A 14-month-old boy had episodic bleeding from a pyogenic granuioma of two months' duration. Note the adhesive on his cheek from many Band-Aid dressings. TABLE 1. Nomenclature of the Pyogenic Granuioma Name
Reference
Botryomycosis hominis Granuioma telangietodes Granuioma pediculatum benignum Granuioma telangiectaticum pediculatum Pseudobotryomycosis Granuioma telangiectaticum Granuioma pyogenicum Fibroangioma Hartzell disease Bloody wart Septic granuioma Hemangiomatous granuioma Lobular capillary hemangioma Eruptive capillary hemangioma
18 19 20 21 21 22-26 27.28 29 30 30 30 31 32 33
A jumbled nomenclature is responsible in part for misconceptions regarding etiopathogenesis {Table 1) (18-33). Pyogenic granuioma of the gingiva, occurring during pregnancy, is called epulis gravidanim or granuioma gravidarum (34-36). In the young pediatric age group., the disorder can occa-
This was a retrospective study of 206 infants and children with pyogenic granuioma registered in the Department of Pathology files. The inclusion criteria for cases culled over 45 years included a histopathologic diagnosis of pyogenic granuioma and sufficient clinical documentation by history, clinical features, and therapy. The histoiogic diagnosis was confirmed by review of the microscopic slides. Twenty-eight inflammatory lesions (granulation tissue), usually wound related, were excluded. The remaining 178 patients were reviewed, focusing on gross and histopathologic descriptions, operative reports, clinical history, and physical examination. The sex, race, and age of each patient were registered. Hypothetical factors of possible pathogenetic significance were recorded; I) preexisting capillary (portwine) stain, 2) dermatologic disorders such as eczematous dermatitis and psoriasis, 3) trauma, 4) viral infection, and 5) insect bite. The size, duration of symptoms, and history of bleeding, ulceration, or exfoliation was noted for each lesion. Exfoliation was defined as spontaneous necrosis and sloughing. The distribution of lesions was categorized according to anatomic location: head and neck, trunk, upper extremity, lower extremity, and perineum. Distribution was also determined according to type of
Patrice et al: Pyogenic Granuloma 269 epidermis, i.e. skin or mucous membrane (intraoral. intranasal, conjunctival, and tympanic membrane). The method of treatment was noted: cautery (chemical or thermal), laser, tangential excision and cautery, and excision and linear closure. Recurrent granulomas were grouped according to the particular unsuccessful treatment. Recurrence after spontaneous necrosis and exfoliation was also recorded. Data from four patients with many granulomas were separated from those on solitary lesions. The clinical data were analyzed for statistically significant relationships among the variables using the chi-square test of independence. Light Microscopy Hematoxylin and eosin-stained tissue for each of the 206 cases was available in the files. The slides were examined for the following histologic features: character of the endothelial and stromal elements, capillary lobule formation, inflammatory infiltrate, presence of an epidermal collarette, and epidermal ulceration. In addition, nine specimens were fixed in 10% buffered formalin, embedded in paraffin, cut and stained with safranin-0, and examined for mast cells (37). Forty high-power fields (450x) were counted for each of the specimens. The mean number of mast cells plus or minus standard deviation (SD) was calculated for each specimen.
and 17 (9.6%) were diagnosed between the first and the twelfth months of life. The frequency of granulomas declined almost linearly with age; only 4.5% occurred in the 15- to 17-year age group. Sex Of the 178 patients in the study, 107 (60.1%) were male and 71 (39.9%) were female, a ratio of 3:2. Predisposing Factors Table 2 shows the frequencies of various predisposing factors that may be associated with the pathogenesis of pyogenic granuloma. The majority of patients (74.2%) had no history of a preexistent cutaneous condition or trauma. Hypothetical predisposing factors, present in 25.8% of patients, included underlying capillary (port-wine) stain, followed by dermatologic disorders, trauma, localized viral infection, and insect bites. Figure 3 illustrates a pyogenic granuloma arising within a port-wine stain (dermal vascular malformation). Race Of the 135patientsfor whom race was reported, 113 were white. 18 were black, 2 were Hispanic, and 2 were Oriental. Caucasian patients comprised 83.7% of the study group and nonwhite groups accounted for 16.3%.
RESULTS
Lesion Size
Age The mean age of the patients was 6.7 years (SD = 4.9 yrs) and the range of ages was 16.8 years (Fig. 2). The majority of pyogenic granulomas (42.1%) appeared within the first five years of life. Only two infants (i.1%) manifested a lesion at birth. Three (1.7%) developed a lesion within the first month.
The size of the lesion was reported for 160 patients. The mean diameter was 6.5 mm (SD ^ 4.1). The range was 18 mm, with the smallest lesion being 2 and the largest 20 mm in diameter (Figs. 4 and 5). Duration Of the 137 patients for which the duration of lesions was reported, the majority were present one to
42. IK (75)
30.«
TABLE 2. Possible Predisposing Factors for Pyogenic Granuloma
(M) 23.OS (-11)
-1.5K IB)
Figure 2. Distribution of pyogenic granulomas according to age of onset. Most lesions appeared in the 0- to 5-year age group; however, 12.4% occurred before 12 months, and only 2.8% within the first month of life.
Condition
Number of Patients
None Port-wine stain Dermatologic disorder Trauma Viral infection Insect bite Totals
132 16 14 12 2 2 178
74.2 9.0
7.9
6.7 LI LI 100.0
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Pediatric Dermatology Vol. 8 No. 4 December 1991
Figure 3. Pyogenic granuloma often occurs in an area of dermal capillary malformation {Left) A 12-year-old girl with port-wine stain of the left cheek (second division trigeminal nerve); note the tiny vascular spot within the stain. (Right) Two weeks later the pyogenic granuloma is florid.
= 7.2) and 2.0 months, respectively, and the range was 71.9 (minimum 5 days, maximum 6 yrs). Anatomic Location
Figure 4. A 1.5-year-old with two-month history of an oozing, crusted, pyogenic granuloma of the lower eyelid.
three months before treatment, regardless of anatomic location. The standard deviation for duration was greater than the mean because of outlying data points. Therefore, the median value was also calculated. The mean and median duration was 3.8 (SD
Two-thirds of pyogenic granulomas were located in the head and neck area, followed by trunk, upper extremity, and lower extremity (Fig. 6). Within the head and neck region, the most frequent sites were the cheek (28.8%), oral cavity (13.5%). scaip (10.8%), forehead (9.9%), and eyelid and lips (both 9.0%). In this study, 88.2% (n - 157) lesions occurred on skin and 11.8% (n ^ 21) on mucous membrane. One appeared on the mucous membrane of the nose and another on the tympanic membrane. Lesions of the posterior and anterior trunk occurred with approximately equal frequency. The majority of lesions of the upper extremity were on the shoulder (43.5%), followed by the hand and fingers (30.4%) and upper and lower arm (26.1%). Lesions of the lower extremity were located with similar frequency on the thigh, calf, foot, and toes.
Patrice et al: Pyogenic Granuloma
271
ANATOMIC DISTRIBUTION OF SOLITARY PYOGENIC GRANULOMA
%Lesions Conjunct ivo
Upptr Extremity-
Perineum-0
Lam-Extremity- SO
Figure 5. A 12-year-old boy with a four-month history of a tiny, 3-mm, pedunculated pyogenic lesion of the anterior neck. Bleeding and Ulceration
Bleeding occurred in 104 (64.2%) of 162 patietits. Ulceratioti was present in 61 (36.3%) of 168 patients. Treatment and Recurrence
None of the 149 lesions treated by surgical excision recurred. However, the recurrence rate was 43.5% for 23 lesions treated by tangential excision and cautery {n = 16) or cautery alone in = 7). Six lesions, all of which were located on the face, underwent necrosis and exfoliation; five recurred. No lesions were treated by laser in this series. Recurrence with multiple lesions occurred in four treated patients (ranging in age from 23 mo-6.5 yrs). These satellite lesions were 1 to 3 mm in diameter and were located at a distance of up to 5 cm away from the original granuloma. The majority of recurrent granulomas had been treated by cautery or tangential excision and cautery. They were
Figure 6. Anatomic distribution of solitary pyogenic granuloma in 178 patients. Two-thirds of lesions occurred in the head and neck region, particularly on the cheek.
small, and correlations between specific treatment modalities and recurrence, with or without satellite lesions, was not statistically significant. Four patients had multiple granulomas. ln three of them, the lesions occurred in pairs, were of equal size, and were located at a distance of 0.5 to 1 cm apart. The fourth patient, a 2-month-otd boy, was born with numerous granulomas ranging in size from 0.4 lo 4.0 cm in diameter and involving the head and neck, trunk, upper and lower extremities, and perianal area (Fig. 7). Histopathology
The typical low-power microscopic appearance of pyogenic granuloma was a well-circumscribed, exo-
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the deeper layer, particularly in lesions with an intact epidermis. With high-power magnification, the immatureappearing capillaries were lined with activeappearing, plump, endothelial cells. The vasoproUferative endothelium exhibited occasional mitotic figures; there was no pleomorphism or atypia. In the nine lesions studied, the mean number of mast cells per high-power field was 3.16 (SD = 2.33). DISCUSSION Clinical Features
Figure 7. Rare instance of large and small multiple pyogenic granulomas in a 2-month-old boy that were present at birth.
phytic mass attached to a narrow stalk, consisting of aggregates of proliferating capillaries located within an edematous matrix (Fig. 8). The epidermal surface often evidenced focal areas of atrophy or frank ulceration. usually present at the summit of the lesion. Several lesions were slightly undermined at the base by the inward growth of acanthotic epithelium, the so-called epithelial collarette. Different histopathologic patterns were seen in the superficial and deep components of these lesions. Immature capillaries with interspersed fibroblastic tissue (resembling granulation tissue) were present within the edematous stroma of the superficial lesion. However, the deeper portions consisted of proliferating masses of capillaries arranged in a distinctive iobular pattern. Some lobules extended into the deep dermis. The stroma of the deeper component was more dense and fibrous. Capillaries located in various levels of the dermis were poorly canalized. An infiltrate of lymphocytes and plasma cells was noted occasionally within the stroma of the superficial region but was usually absent from
Clinical characteristics are sufficient to distinguish pyogenic granuloma from other benign proliferative vascular lesions, particularly infantile hemangioma. Pyogenic granuloma begins as an erythematous macule that evolves into a papule. The lesion grows rapidly and frequently becomes pedunculated, or it may remain sessile. The integrity of the overlying epidermis determines the granuloma" s color and texture. With an intact epidermis, the lesion is bright red and smooth. When ulcerated it is covered by a dark, adherent crust or has a moist, granular surface (17). The majority of pyogenic granulomas manifested in children older than 1 year. In only two patients were solitary iesions, and in one patient multiple granulomas. present at birth. The mean diameter of pyogenic granulomas was 6.5 mm, with a range between 0.2 and 2 cm. Over 75% were less than 1 cm. A history of spontaneous ulceration and bleeding is commonplace; the latter occurred in two-thirds of patients in our study. The lesions were 1.5 times more common in males. Other investigators also reported a slight preponderance of males in patients under 18 years of age and an increased frequency in females between ages 18 and 39 years (32). The majority of granulomas occurred in white patients (83.6%); this reflects the racial distribution of patients seen in our institution. The lesions were present more commonly on the upper extremity than the lower extremity. Perhaps this anatomic distribution is related to the density of cutaneous vascularity; that is, greatest in head and neck followed by the trunk and extremities (38). Histologic Features
Review of the literature suggests that pyogenic granulomas can be distinguished from other acquired vascular lesions by microscopy, including
Patrice et al: Pyogenic Granuioma
273
Figure 8. Light microscopy of pyogenic granuioma. (Left) Low-power demonstrates the weii-circumscnoea mass of proliferating capillaries in an edematous matrix. Note the epithelial coUarette at the base, and the intact epidermis. (Hematoxylin & eosin; magnification 40x.) (Right) High-power photomicrograph of pyogenic granuioma demonstrates the capillary-size channels encased in myxoid to fibromyxoid stroma. (Hematoxylin & eosin; magnification 200 X.)
immunocytology, and by ultrastructural methods. Pyogenic granuioma characteristically exhibits a histologic lobular arrangement of capillaries within the deep portion of the lesion. Mills et ai (32) emphasized that these lobules are the critical identifying feature of the lesion, rather than the presence of an epithelial collarette, ulceration. inflammatory infiltrate, or edematous matrix. They proposed the term lobular capillary hemangioma to replace pyogenic granuioma (32). Mast cells have long been recognized as participants in angiogenic lesions, particularly neoplasms. We found normal levels in the nine specimens of pyogenic granuiomas that were stained for mast cells. This is in contrast to the markedly elevated number of mast celJs typically seen in proliferative phase hemangiomas (37). Immunohistochemical staining of the endothelial cells of pyogenic granuiomas with factor VIIIrelated antigen and ulex europeas agglutinin lectin was reported to be negative (39,40). The lesion
stains strongly for smooth muscle actin within the proliferating celiular element (41). This suggests that the pericyte is the major hyperplastic cellular component. This staining pattern may also help to differentiate pyogenic granuiomas from infant hemangiomas and borderline malignant vascular tumors such as epithelioid hemangioendothelioma of the oral cavity (42). Ultrastructural studies have shown that pyogenic granuiomas demonstrate connective tissue synthesis with significant production of giycosaminoglycan, fibroblasts and pericytes with well-developed rough endoplastic reticuium. and immature extracellular collagen fibers (43). Although endothelial nuclei may be elongated and lobulated, these cells appear to have normal structure and organelles., with little evidence of increased biosynthetic orcatabolic activity and relatively normal basement membranes (43). Ultrastructura! analysis of several granuiomas in our series demonstrated multiplica-
274 Pediatric Dermatology Vol. 8 No. 4 December 1991 tion of basal lamellae, as would be expected in lesions with increased endothelial turnover (44). Tufted angioma is a newly recognized, acquired, vasoproliferative lesion of childhood that is closely related to but clinically and histologically distinguishable from pyogenic granuloma (45,46). Tufted angioma grows slowly; it appears within the first five years of life but rarely before age 1 year. The usual location is the upper chest, neck, and shoulder, not the face or scalp. The lesions are plaquelike, dull red. macular or papular, and 2 to 5 cm in diameter. Microscopically, there are circumscribed lobules of hypertrophied capillaries within the mid to lower dermis. In contrast to pyogenic granuloma. the lobules contain closely packed endothelium with few dilated lumina, there is a mucin-rich stroma, and lymphatic-like channels are seen adjacent to and at a distance from the capillary tufts. Etiology The etiology of this lesion remains unknown. Several investigators hypothesized that it is a hyperproliferative vascular response to infective organisms of low virulence. The entity was first described in 1897 by Poncet and Dor, who believed thai the etiologic organisms were fungi (18). In the early nineteenth century, Crocker and Hartzel! applied the term granuloma pyogenicum. believing the lesion to be a localized bacterial infection (27.28). A viral etiology has also been suggested but has never been documented in case reports (4). Some authors suggest that the granuloma arises from trauma to the skin or mucous membrane, healing abnormally with excessive formation of granulation tissue (21). However, in our study only 7% of the patients gave a history of trauma preceding the onset of a lesion, and only 1.2% had a history of viral infection. Pyogenic granuloma can be categorized as a disorder of angiogenesis of unknown etiology. Its pathogenesis involves a neovascular response to an angiogenic stimulus, promoting predominant growth of pericytes with less effect on endothelial cells. The fact that it frequently occurs within a port-wine stain and has a predilection for the head and neck suggests that the unknown angiogenic stimulus is most likely to be triggered in dense or dilated vascular beds (47). Approximately 9% of the patients in this study had a history of the granuioma arising within a port-wine stain; an underlying dermatologic disorder, such as psoriasis and eczematous dermatitis, accounted for 7.6% of patients. Perhaps the increased infiammatory angiogenesis
associated with these conditions also stimulates pericytic hyperplasia. Endocrine factors have also been suggested as contributory to vascular proliferation in pyogenic granuloma (48). Treatment
We could not document the frequency with which pyogenic granuloma may exfoliate and never require treatment. All lesions in this study were removed by surgical excision, with the exception of a single one that underwent spontaneous necrosis and subsequent healing without recurrence. It is possible that some of these lesions could have regressed spontaneously at some future time, yet, mature granulomas tend lo persist. Lesions of long duration, ranging from 6 to 20 years, are reported (21). The usual treatment is cautery with silver nitrate, electrodesiccation. curettage, or tangential excision and cautery. In this retrospective study, the recurrence rate was 43.5% for 23 lesions treated by cautery alone (i.e., chemical or thermal) or after tangential excision and cautery. Curiously, four granulomas recurred with multiple satellite lesions. a rare phenomenon, previously documented (6-16). A recurrence rate of 16% is reported for intraoral lesions treated by superficial excision (49). However, only a prospective study would best document the effectiveness of primary curettage and/or cautery. In our study, no recurrences were seen after full-thickness excision and linear closure. Argon and pulsed dye lasers, which have been successful in the treatment of port-wine stain, have had equivocal results in the therapy of pyogenic granulomas. Vascular proliferatioti below the papillary dermis is beyond the range of argon laser, which only penetrates 1.0 to 1.5 mm beneath the epidermis. Results with the pulsed dye laser also have been disappointing. In theory, the neodymium:yttrium-argon-gamet laser should have sufficient penetration (4-6 mm) to destroy the lesion, however, scarring can be esthetically unacceptable with this modality. ACKNOWLEDGMENTS
The authors extend their gratitude to Richard A. LaBrie, Ed.D., for his statistical analysis of our data. We are indebted to Harry P. W. Kozakewich, M.D.. for his guidance in evaluating the histopathologic specimens, and to A. J. Man"ogi, M.D., for his contributions to the discussion of histopathology.
Patrice et al: Pyogenic Granuloma
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mal dermis in pyogenic granuioma: histochemicat and ultrastructural observations. J Am Acad Dermatol 1980;2:132-142. 44. Vrako R. Basal lamina scaffold—anatomy and significance for maintenance of orderly tissue structure: A review. Am J Surg Pathol 1974;77:313-346. 45. Padilla RS, Orkin M, Rosai J. Acquired "tufted" angioma (progressive capillary hemangioma): a distinctive clinicopathologic entity related to lobular capillary hemangioma. Am J Dermatopathol 1987;9: 292-300. 46. Wilson JE, Orkin M. Tufted angioma (angioblas-
toma): a benign progressive angioma. not to be confused with Kaposi's sarcoma or low-grade angiosarcoma. J Am Acad Dermatol 1989;20:214-225. 47. Swerlick RA. Cooper PH. Pyogenic granuioma (lobular capillary hemangioma) within port-wine stains. J Am Acad Dermatol 1983;8:627-630. 48. Leyden J. Master G. Oral cavity pyogenic granuioma. Arch Dermato! 1973;lQ8:226-228. 49. Bhaskar SN. Jacoway JR. Pyogenic granuioma: clinical features, incidence, history, and result of treatment: report of 242 cases. J Oral Surg 1966:24:391398.
