Intravenous pyogenic granuloma. Case report with ultrastructural findings

Intravenous Pyogenic Granuloma Case Report with Ultrastructural Findings THOMAS M. ULBRIGHT, MD,* AND DANIEL J. SANTA CRUZ, M D t

A nodule, attached to the intimal surface of the external jugular vein of a 12-year-old boy, showed the light microscopic features of a pyogenic granuloma. The small muscular arteries in the adventitia contained numerous tufted intraluminal capillaries, and it is possible that the angiomatous proliferation within the jugular vein originated from the vasa vasorum, with subsequent growth into the venous lumen. This intraluminal growth dispersed the tunica elastica into the pyogenic granuloma. Ultrastructural examination showed, the lesion to be composed of capillaries lined by low and cuboidal endothelial cells, with occasional pericytes surrounded by focally multiple basal laminae. In some locations, the capillary endothelial basal lamina abutted directly on collagen with no intervening pericyte. In the stroma of the tumor there were cells with myofibroblastic features. This benign intravascular growth should be distinguished from other benign but atypical intravascular and vascular proliferations. Cancer 45:1646-1652. 1980.

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Recently, Cooper et ~ 1described . ~ 18 cases of intrahas been made in recent venously occurring pyogenic granuloma, a lesion preyears in recognizing and understanding benign viously unrecognized as a clinicopathologic entity. A and malignant vascular tumors. Wilson Jones,”’ Reed et and Rosai et al.,‘“ have described the clinicosimilar case was illustrated by Wilson Jones? who pathologic features of cutaneous angiosarcomas and, commented on its resemblance to a pyogenic granin so doing, have brought attention to the deceptive uloma. In this report, we describe another such case and its electron microscopic appearance. histology of these malignant tumors. Benign-appearing areas often exist in angiosarcomas and cause conCase Report fusion with truly benign conditions. On the other hand, A 12-year-old boy was seen at the St. Louis Children’s a variety of benign vascular proliferations may be Hospital Clinic complaining of a “knot” on the right side histologically confused with angiosarcomas. These inof the neck of two month’s duration. The patient‘s mother clude intravascular papillary endothelial hyperplasia’j5 initially felt that the knot was “part of a neck vein,” (Masson’s pseudoangiosarcoma18) which is probably but brought the boy to be evaluated when she thought that an exuberant, organizing thrombus ,5,27 pyogenic granthe lesion had moved cephalad. The mass was nontender, uloma with satellite nodules,’ pseudo-Kaposi sarand the remainder of the clinical history was unremarkable. coma,y and proliferations of histiocytoid endothelial On physical examination, a 1.5-cm nontender, firm, and cells25: intravenous atypical vascular ~ r o l i f e r a t i o n , ~ ~mobile nodule was palpated in the subcutaneous tissues of pseudopyogenic granuloma,8-33 and angiolymphoid hythe right side of the neck. No other mass was found, and perplasia with e ~ s i n o p h i l i aThe . ~ latter two conditions the remainder of the physical examination was unremarkable. After a trial of antibiotic therapy which reare morphologically similar entities which have some sulted in no decrease in size of the neck mass, surgical clinical distinctions. ONSIDERABLE PROGRESS

From the Department of Pathology, Division of Surgical Pathology, Washington University School of Medicine and Barnes Hospital, St. Louis, Missouri. * Chief Resident, Department of Pathology. iAssistant Professor of Pathology and Surgical Pathology. Address reprints: D. Santa Cruz, MD, Division of Surgical Pathology; Barnes Hospital; Barnes Hospital Plaza; St. Louis, Missouri 631 10. The authors wish to thank Drs. Walter Bauer and Philip Prioleau for helpful suggestions concerning the manuscript. Accepted for publication April 3, 1979.

excision was performed. Exploration revealed involvement of the posterior portion of the external jugular vein and en bloc dissection was performed with resection of a small portion of the external jugular vein, in continuity with the cervical mass. The patient remains well a year following surgery. Materials and Methods The specimen was received fixed in 10% neutralbuffered formalin. Cross-sections of the lesion and vein

0008-543x180/0401/166 $0.85 0 American Cancer Society

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were processed for hematoxylin-eosin ( H & E) stains, and iron-gallein H & E elastin stains. A portion of the lesion was then minced and fixed in glutaraldehyde, dehydrated, postfixed in osmium tetroxide, embedded in Spurr, and sectioned on an ultramicrotome. Thin sections were then stained with uranyl acetate and lead citrate and examined in a Philips EM-300 electron microscope. Results Gross Results

The excised portion of right external jugular vein showed a 1-cm polypoid projection of pink-gray tissue attached to the intimal surface of the vein by a thin stalk. Light Microscopy Results

Histologically, the lesion consisted of an intravascular projection of tissue attached to the luminal surface of the vein wall (Fig. 1). At higher magnification, the polypoid projection demonstrated a biphasic composition. The most prominent component consisted of a proliferation of tufted capillaries, and in addition, there were large areas of a poorly cellular stroma. The capillaries were small and lined by prom-

FIG. I . Pyogenic grenuloma, attached by a stalk, projects from venous wall (right side) into the lumen of the vein. Foci of capillaries and myxoid stroma are apparent in the pyogenic granuloma (iron gallei" & E; x8) (Washington u. Neg. 78-7528),

inent endothelial cells which were approximately equally distributed throughout the tumor although somewhat more abundant in the central and basal portions. The stromas had a myxoid quality and occasionally contained elongated spindle cells (Fig. 2). This intravascular nodule appeared to be a pyogenic granuloma, but lacked an inflammatory component and surface ulceration. Stains for elastic tissue showed disruption of the elastic fibers along the area of attachment of the pyogenic granuloma with the vein wall. This finding

FIG.2. Foci of capillaries show endothelium lining vascular lumina of varying sizes with endothelial cells and pericytes present in the denser perithelial connective tissue. Elongated spindle cells are apparent in the less dense myxoid stroma away from the capillaries (iron gallein H & E, x 150) (Washington U. Neg. 78-7535).

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FIG.3 . Intrasvascular proliferation of capillaries is seen in the venous adventitia. This proliferation is felt to be within small arteries. Disrupted elastic fibers are apparent surrounding these expanded vessels on the left while they appear intact around the vessel on the right (iron gallein H & E x150) (Washington U . Neg. 78-9308).

appeared to be the result of proliferation of capillaries within small muscular arteries in the adventitia (Fig. 3). With this proliferation of capillaries, portions of the venous tunica elastica were carried into the intravenous mass, and thus elastic fibers were found well within the tumor and far from the venous wall. Electron Microscopic Results

The capillary and stromal components seen by means of light microscopy were more apparent on ultrastructural examination. The capillaries were composed of endothelial cells surrounding vascular lumina. The distribution of the cells were uneven, giving the vessels a more cellular appearance than a normal capillary. Slit-like lumina were occasionally seen (Figs. 4, 5 ) . Most of the endothelial cells had relatively flat contours, but some were more cuboidal in shape, protruding into the lumen in a hobnail pattern (Fig. 5). The endothelial cells had finely dispersed nuclear chromatin which clumped along the nuclear membrane and showed cytoplasmic micropinocytotic vesicles along the luminal and basal portions. In addition, the cytoplasm of the endothelia showed occasional mitochondria, scattered ribosomes, and rare WeibelPalade bodies. Occasionally, cells showed numerous cytoplasmic microfilaments (Fig. 6), although the

majority displayed few or none. Adjacent endothelial cells were joined by tight junctions and were surrounded by basal laminae which also surrounded occasional pencytes or abutted directly on collagen fibrils. The basal lamina around the endothelial cells showed frequent multiplication with two or more laminar layers present. In the myxoid areas of the tumor there were finely dispersed collagen fibrils. Scattered among the collagen fibrils were elongated cells having convoluted nuclei, one or more nucleoli, and dispersed chromatin which were clumped along the nuclear membrane (Fig. 7). The cytoplasm of these cells had abundant rough endoplasmic reticulum. Numerous parallel arrays of microfilaments were distributed axially along the cellular membrane, with occasional fusiform densities. A discontinuous basal lamina surrounded these cells. The cell membrane showed focal condensations representing primitive cellular attachments. Discussion

Pyogenic granuloma has been recognized for a number of years.16 It classically occurs on epitheliallined surfaces such as skin, and oral and genital mucosa. As its name denotes, it was considered to be a reactive lesion secondary to trauma and pyogenic

FIG.4. Capillary lined by flat endothelial cells partially surrounded by multiplicated basal laminae and showing relatively radiolucent perithelial cell (left). Lumen has focal slit-like configuration ( ~ 3 2 0 0 (EM ) Neg. 32596).

FIG.5. Cuboidal endothelial cells with a hobnail protrusion into capillary lumen. Another slit-like lumen is present (upper left). Multiple layers of basal lamina material surround one capillary and intermingle with collagen fibrils ( ~ 3 2 0 0 (EM ) Neg. 32599).

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FIG.6. Cytoplasmic microfilaments are present in endothelial cell. A Weibel-Palade body is seen (upper right), as well as micropinocytotic vesicles along the luminal border ( x 10,300) (EM Neg. 29860). Insrt. Tight junctions join adjacent endothelial cells. Two Weibel-Palade bodies arc present in cytoplasm of each cell ( x 10,300) ( E M Neg. 32594).

infection. A peculiar association with pregnancy was also noted in the oral lesions.20 More recently, this etiologic explanation has been questioned, and the lesion is thought to be a true angiomatous neoplasm associated with secondary inflammatory changes.I5 In accordance with the neoplastic theory, its occurrence at sites not usually subject to trauma and pyogenic infection should not be surprising. The light microscopic features are characteristic and include numerous capillaries growing in a sparsely cellular, edematous, collagenous stroma, which may contain numerous inflammatory cells with secondary ulceration of the lesion. Cooper et reported 18 cases of nodules in the veins of the neck or upper limbs which had the histopathologic features of pyogenic granuloma, but lacked the superficial edema and inflammation. The electron microscopic findings in this case are consistent with the observations of Eady and Wilson Jones8 of the more classically located pyogenic granuloma. They noted that the capillaries of pyogenic granuloma were lined by typical-appearing endothelial cells.' Weibel-Palade bodies,30cytoplasmic micropinocytotic vesicles,2Yand endothelial micro filament^^^,^^ are present in normal human vessels, and their presence in this case supports the conclusion that the vessels had a normal structure. The interstitium of the tumor showed cells which had the ultrastructural features of myofibroblasts, as described in granulation tissue by Gabbiani et a l ,l 1

and Ryan et These cells, which have characteristics of both smooth-muscle cells and fibroblasts,I4 have been described in a variety of pathologic conditions frequently associated with contraction such as Dupuyten's contracture12 and stenosing tenosynovitis,21 as well as in a wide variety of tumors and tumor-like conditions. l 4 Their occurrence in juvenile nasopharyngeal angiofibroma is particularly appropriate t o this case because its components are, similarly, both vascular and myofibroblastic, although the vessels of angiofibromas have thicker walls and by ultrastructure are surrounded by collars of smooth muscle .28 The intravascular proliferation of angiomatous elements raises the issue of differential diagnosis. Rosai and Akermanz3have described the occurrence of proliferating endothelial cells within the lumina of veins of the lower dermis and underlying soft tissues. Frequently there were areas within such lesions that contained atypical acidophilic cells resembling keratinocytes, although there were also areas with a more obvious endothelial origin, as well as transitional zones. This lesion was designated intravenous atypical vascular proliferation (IAVP) and differs from intravenous pyogenic granuloma by the greater cellularity and atypia of the proliferating endothelial cells in the former, which may make it difficult to discern vessel formation without careful search. Another differential feature is the involvement of multiple veins, usually of medium size. More recently Rosai ef a[.';' have placed this

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FIG.7. Cells present in the myxoid zones of tumor show convoluted nuclei, with nucleoli clearly visible in one cell. Rough endoplasmic reticulum is present in these cells, as well as parallel arrays of microfilaments along the cytoplasmic borders. Occasional dense condensations are present in these arrays of microfilaments, and the cells are partially surrounded by a basal lamina. The stroma is loose and edematous, showing scattered collagen fibrils, ( ~ 3 2 0 0 (EM ) Negs. 29862 and 29863).

lesion in the category of vascular proliferations characterized by histiocytoid endothelial cells-a cell type which has distinctly different morphologic and histochemical characteristics from the endothelial cell of intravenous pyogenic granuloma. They regard many entities. previously felt to be distinct, as morphologic and topographic variants of proliferations of histiocytiod endothelial cells. Thus, other lesions such as angiolymphoid hyperplasia with e o ~ i n o p h i l i aatyp,~ ical or pseudo-pyogenic granuloma,"3 hemangioendothelioma and low-grade angiosarcoma of bone, and benign angioreticuloma of the heart are felt by Rosai et al. to constitute a spectrum of diseases characterized by the proliferation of this distinctive cell. The completely intravascular tumors, as well as the cutaneous and soft-tissue lesions which have an intravascular component, are therefore differentiated from intravenous pyogenic granuloma by the different light microscopic features of the endothelial cells.25Furthermore, the ultrastructural features of the histiocytoid endothelial cells are distinctly different;",x"5 the cells are enlarged and contain increased numbers of cytoplasmic organelles and cytoplasmic microfilaments. They are plump cells, frequently displaying intracellular lumina-an ultrastructural feature characteristic of histiocytoid endothelial cell^.'^ Intravascular papillary

endothelial hyperplasia (IPEH) is regarded by some investigators' as a variant of IAVP. other^'^,'^,^^ believe it is a distinct entity. It should be differentiated from intravenous pyogenic granuloma by the usually distinctive papillary nature of the tumor. Furthermore, the association with thrombosis, whether a primary or secondary event, can be helpful by demonstrating fibrin within the lesion. This differential feature also applies to more typical organizing thrombi. Ultrastructurally , the peculiar filamentous-rich subpopulation of pericytes described in IPEHI7 was not found in this case of intravenous pyogenic granuloma, although the description of these cells was similar to the myofibroblasts present in the myxoid stroma. Intravenous pyogenic granuloma is to be distinguished from the hemangiomatous pattern of glomus jugulare which may also present as an intravascular mass.4The lack of an organoid pattern of nested glomus (chief) cells between the capillaries is the single most important differential feature.13 Ultrastructural features of glomus jugulare, including neurosecretorytype granules within glomus cells,2 are lacking. Briefly, differentiating other lesions does not pose a great problem. Pseudo-Kaposi sarcoma results from the capillary and fibroblastic proliferation secondary

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to an arteriovenous f i ~ t u l aIt . ~is not an intravascular proliferation, which provides an essential differential feature from intravenous pyogenic granuloma, and a similar argument applies to Kaposi’s sarcoma itself. Interstitial hemosiderin deposition is not present in intravenous pyogenic granuloma. Intravenous pyogenic granuloma is a rare benign lesion which probably arises from neoplastic proliferation of capillaries within small adventitial arteries. It seems reasonable to attribute the intravenous occurrence of pyogenic granuloma to a proliferation of the endothelium of the parent vein’s vasa vasorum with capillary formation. This idea is supported by the finding of capillaries of identical appearance to those of the whole lesion within the adventitial muscular arteries, and by the disruption of the venous elastic fibers which must result from intraluminal growth from this adventitial focus. REFERENCES 1. Barr, R. J., Graham, J. H., and Sherwin, L. A.: Intravascular papillary endothelial hyperplasia. Arch. Dermatol. 1 14:723-726, 1978. 2. Capella, C . , and Solcia, E.: Optical and electron microscopical

study of cytoplasmic granules in human carotid body, carotid body tumors, and glomus jugulare tumors. Virchows Arch. Aht. B . Z d p a t h . 7:37-53, 1971. 3. Castro, C., and Winkelmann, R. K.: Angiolymphoid hyperplasia with eosinophilia in the skin. Cancer 34:1696-1705, 1974. 4. Chretien, P. B., Engelman, K., Hoye, R. C., and Gellhoed, G. W.: Surgical management of intravascular glomus jugulare tumor Am. J . Surg. 122:740-743, 1971. 5 . Clearkin, K. P., and Enzinger, F. M.: Intravascular papillary endothelial hyperplasia. Arch. Puthol. Lab. Med. 100:441-444, 1976. 6. Cooper, P. H., McAlister, H. A,, and Helwig, E. B.: Intravenous pyogenic granuloma. A study of eighteen cases. A m . J . Surg. Puthol. 3:22 1- 228, 1979. 7. Coskey, R. J . , and Mehregan, A . H.: Granuloma pyogenicum with multiple satellite recurrences. Arch. Dermurol. 96:71-73, 1967. 8. Eady, R. A. J., and Wilson Jones, E.: Pseudopyogenic granuloma: Enzyme, histochemical, and ultrastructural study. Hum. Pathol. 8:653-668, 1977. 9. Earhart, R. N . , Aeling, J. A., Nuss, D. D., and Melette, J. R.: Pseudo-Kaposi sarcoma. Arch. Dermurol. 110:907-910, 1974. 10. Enzinger, F. M.: Letter to the editor. Arch. Patho/. Lab. Mrd. 101:450, 1977. 1 I. Gabbiani, G., Ryan, G. B., and Majno, G.: Presence of modi-

fied fibroblasts in granulation tissue and possible role in wound contraction. Experienriu 27:549-550, 1971. 12. Gabbiani, G., and Majno, G.: Dupuytren’s contracture;

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intravascular hemangioendothelioma”: A lesion often mistaken for angiosarcoma. Cancer 38: 1227- 1236, 1976. 19. Ludatscher, R. M.: Ultrastructure of human dermal blood vessels with special reference to the endothelial filaments. Virchows Arch. B. Cell Path. 27:347-357, 1978. 20. MacVicar, J., and Dunn, M. F.: Pregnancy tumor ofthegums. J . Obstet. Gynecol. Br. Commonwealth 76:260-263, 1969. 21. Madden, J. W., Carlson, E. C., and Hines, J.: Presence of modified fibroblasts in ischemic contracture of the intrinsic musculature of the hand. Surg. G.vneco1. Ohstet. 140:509-516, 1975. 22. Reed, R. J., Palomeque, F. E., Hairston, M. A. 111, and Krementz, E. T.: Lymphangiosarcomas of the scalp. Arch. Dermato/. 94:396-402, 1966. 23. Rosai, J., and Akerman, L. R.: Intravenous atypical vascular proliferation. Arch. Dermatol. 109:714-717, 1974. 24. Rosai, J., Sumner, H. W., Kostianovsky, M., and PerezMesa, C.: Angiosarcoma of the skin. A clinicopathologic and fine structural study. Hum. Pathol. 7:83-109, 1976. 25. Rosai, J., Gold, J., and Landy, R.: Proliferative diseases of histiocytoid endothelial cells. A unifying concept embracing several previously described entities of skin, soft tissue, large vessels, bone, and heart. Hum. Pccthol. 10:707-730, 1979. 26. Ryan, G. B., Cliff, W. J . , Gabbiani, G., Irle, C., Montandon, D., Statkov, P. R., and Majno, G.: Myofibroblasts in human granulation tissue. Hum. Pathol. 5:55-67, 1974. 27. Salyer, W. R., and Salyer, D. C.: Intravascular angiomatosis: Development and distinction from angiosarcoma. Cancer 36:9951001, 1975. 28. Taxy, J . B.: Juvenile nasopharyngeal angiofibroma. Cancer 3 9 1044- 1054, 1977. 29. Waldo, E. D., Vuletin, J. C., and Kaye, G. I.: The ultra-

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