Pyogenic Granuloma (Lobular Capillary Hemangioma)

Clinical Findings

• •

  The majority of cases (80%) occur below 40 years of age with the highest prevalence in the second decade; it is often associated with local irritation or trauma and pregnant women may develop these on the gingiva (see Chapter 5 ).

• •

  It appears as a purple-to-red nodule, sessile or pedunculated, usually on the gingiva (75%–80% of cases), lips (especially upper), and tongue, sometimes with a history of bleeding ( Fig. 6.1A–C ).

  

  (A) Pyogenic granuloma of the upper vermilion. (B) Pyogenic granuloma of the hard palatal mucosa. (C) Pyogenic granuloma of the tongue, ulcerated. (D) Reactive fibrovascular polyp, cyclosporine-induced after stem cell transplantation.

• •

  Patients on cyclosporine after stem cell transplantation develop pyogenic granuloma-like lesions (fibrovascular polyps) on the buccal mucosa or tongue rather than the gingiva ( Fig. 6.1D ).

Etiopathogenesis and Histopathologic Features

Pyogenic granuloma is a reactive, nonneoplastic proliferation of endothelial cells and capillaries in response to local injury (such as plaque accumulation) where there is impaired wound healing and vascular growth driven by FLT4 (a tyrosine kinase receptor) and the nitric acid pathway. It is sometimes referred to as lobular capillary hemangioma, but unlike infantile capillary hemangioma, it does not react with glucose transporter-1 (GLUT-1).

• •

  There is a proliferation of endothelial cells and capillaries (often dilated), often but not always in a lobular pattern, usually with overlying ulcer, and acute and chronic inflammation; mitotic figures are not uncommon ( Figs. 6.2 and 6.3 ); capillaries are surrounded by smooth muscle actin (SMA)+ pericytes.

  

  Pyogenic granuloma. (A) Typical lobular architecture with many dilated capillaries. (B) Cellular proliferation of endothelial cells and dilated capillaries.

  

  Pyogenic granuloma of lip. (A) Diffuse cellular proliferation of endothelial cells with dilated capillaries. (B) Variably dilated capillaries. (C) Benign endothelial cells and mitotic figure (center) . (D) Capillaries are surrounded by a layer of pericytes that are positive for smooth muscle actin.

• •

  Some lesions may show significant reactive atypia with hyperchromatic and pleomorphic nuclei ( Fig. 6.4 ).

  

  Pyogenic granuloma. (A) Ulcerated polypoid nodule. (B) Retiform proliferation of vessels. (C) Moderate atypia of endothelial cells.

• •

  Older lesions sclerose and become fibrous nodules or fibromas, especially those on the gingiva ( Fig. 6.5 ).

  

  Pyogenic granuloma, sclerosing. (A) Vague lobular architecture with intervening fibrosis. (B) Fibrous tissue infiltrates between and into lobules. (C) Clusters of endothelial cells and capillaries.

• •

  Lesions are CD31+ and CD34+ but GLUT-1−.

Differential Diagnosis

• •

  Edematous polypoid masses of granulation tissue seen in stem cell transplant recipients on calcineurin inhibitors such as cyclosporine are better diagnosed as reactive fibrovascular hyperplasia or fibrovascular polyps.

• •

  True infantile capillary hemangioma shows a cellular proliferation of endothelial cells and capillaries that are positive for GLUT-1+ and regress over time (see Fig. 5.22 ).

Management and Prognosis

• •

  Excision is the treatment of choice with recurrence in 5% to 6% of cases.

Clinical Findings

• •

  The majority of cases (80%) occur below 40 years of age with the highest prevalence in the second decade; it is often associated with local irritation or trauma and pregnant women may develop these on the gingiva (see Chapter 5 ).

• •

  It appears as a purple-to-red nodule, sessile or pedunculated, usually on the gingiva (75%–80% of cases), lips (especially upper), and tongue, sometimes with a history of bleeding ( Fig. 6.1A–C ).

  

  (A) Pyogenic granuloma of the upper vermilion. (B) Pyogenic granuloma of the hard palatal mucosa. (C) Pyogenic granuloma of the tongue, ulcerated. (D) Reactive fibrovascular polyp, cyclosporine-induced after stem cell transplantation.

• •

  Patients on cyclosporine after stem cell transplantation develop pyogenic granuloma-like lesions (fibrovascular polyps) on the buccal mucosa or tongue rather than the gingiva ( Fig. 6.1D ).

Etiopathogenesis and Histopathologic Features

Pyogenic granuloma is a reactive, nonneoplastic proliferation of endothelial cells and capillaries in response to local injury (such as plaque accumulation) where there is impaired wound healing and vascular growth driven by FLT4 (a tyrosine kinase receptor) and the nitric acid pathway. It is sometimes referred to as lobular capillary hemangioma, but unlike infantile capillary hemangioma, it does not react with glucose transporter-1 (GLUT-1).

• •

  There is a proliferation of endothelial cells and capillaries (often dilated), often but not always in a lobular pattern, usually with overlying ulcer, and acute and chronic inflammation; mitotic figures are not uncommon ( Figs. 6.2 and 6.3 ); capillaries are surrounded by smooth muscle actin (SMA)+ pericytes.

  

  Pyogenic granuloma. (A) Typical lobular architecture with many dilated capillaries. (B) Cellular proliferation of endothelial cells and dilated capillaries.

  

  Pyogenic granuloma of lip. (A) Diffuse cellular proliferation of endothelial cells with dilated capillaries. (B) Variably dilated capillaries. (C) Benign endothelial cells and mitotic figure (center) . (D) Capillaries are surrounded by a layer of pericytes that are positive for smooth muscle actin.

• •

  Some lesions may show significant reactive atypia with hyperchromatic and pleomorphic nuclei ( Fig. 6.4 ).

  

  Pyogenic granuloma. (A) Ulcerated polypoid nodule. (B) Retiform proliferation of vessels. (C) Moderate atypia of endothelial cells.

• •

  Older lesions sclerose and become fibrous nodules or fibromas, especially those on the gingiva ( Fig. 6.5 ).

  

  Pyogenic granuloma, sclerosing. (A) Vague lobular architecture with intervening fibrosis. (B) Fibrous tissue infiltrates between and into lobules. (C) Clusters of endothelial cells and capillaries.

• •

  Lesions are CD31+ and CD34+ but GLUT-1−.

Differential Diagnosis

• •

  Edematous polypoid masses of granulation tissue seen in stem cell transplant recipients on calcineurin inhibitors such as cyclosporine are better diagnosed as reactive fibrovascular hyperplasia or fibrovascular polyps.

• •

  True infantile capillary hemangioma shows a cellular proliferation of endothelial cells and capillaries that are positive for GLUT-1+ and regress over time (see Fig. 5.22 ).

Management and Prognosis

• •

  Excision is the treatment of choice with recurrence in 5% to 6% of cases.

Clinical Findings

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  Varix (venous lake): This occurs in middle-aged and older adults as a bluish bleb, from a few millimeters to 1 to 2 cm in size, located on the lips, tongue, or buccal mucosa; pressure causes blanching and this is demonstrated by pressing a glass slide onto the lesion so that the vessel empties (diascopy), although this can also be accomplished with a dental instrument; lesions may bleed ( Fig. 6.6A–C ).

  

  (A) Varix of the lower lip mucosa. (B) Same case as in A; varix blanches with pressure. (C) Varix of the left lateral tongue. (D) Bilateral lingual varices of the ventral tongue. (E) Venous malformation of lower lip mucosa. (F) Venous malformation of the left tongue.

  (F, Courtesy Dr. David Feinerman, private practice, Boynton Beach, Fla.)

• •

  Bilateral lingual varicose veins of the ventral tongue are common in older adults ( Fig. 6.6D ).

• •

  Simple venous malformation: These are larger bluish masses usually present at birth; in the oral cavity, they may occur in older patients and are usually several centimeters in size, often involving the underlying muscle; there may be significant deformity ( Fig. 6.6E–F ).

Etiopathogenesis and Histopathologic Features

A varix (venous lake) is a dilated venule that results from loss of elasticity of the muscle around venules (likely postcapillary venules) leading to dilatation of the lumen. Venous malformation is a low-flow lesion that is a developmental malformation of the veins that is caused by local defects of vascular morphogenesis and dysembryogenesis; such malformations are connected to the normal vasculature. They may occur as arteriovenous malformations and are best diagnosed by a thorough clinical examination and ultrasonographic and/or angiographic studies. What used to be known as cavernous hemangioma is now reclassified as a venous malformation by ISSVA.

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  Varix: These are dilated, tortuous, thin-walled vessels with a variable but usually thin muscular coat; valve leaflets may be present ( Figs. 6.7 and 6.8 ); thrombi in various stages of organization are often noted, sometimes with hyalinization, and Masson tumor (intravascular papillary endothelial hyperplasia) is sometimes seen; this is composed of small hyalinized globules containing small capillaries and is surrounded by endothelium ( Figs. 6.9 and 6.10 ).

  

  Varices. (A) Dilated vascular spaces. (B) Spaces are lined by a single layer of endothelium and valve leaflets are present.

  

  Varices. (A) Dilated venules within the muscle. (B) Dilated endothelium-lined space between skeletal muscle fibers.

  

  Varix with thrombus. (A) Attachment of thrombus to the vessel wall is noted. (B) Layers of fibrin and red blood cells with organization. (C) Mitotic activity is not unusual within an organizing thrombus.

  

  Organizing thrombus. (A) Markedly cellular nodule. (B) Nodule consists of mainly endothelial cells with remnants of the thrombus ( left ) and area of hyalinization ( right ). (C) Focus of Masson tumor. (D) Marked hypercellularity with mitotic figure.

• •

  Venous malformation: Many dilated venules of varying sizes are noted, sometimes intramuscular in location without a proliferation of endothelial cells ( Figs. 6.11–6.13 )

  

  Venous malformation with thrombi. (A) Large dilated and congested venules with thrombus (right). (B) Thrombus with hyalinization.

  

  Venous malformation. (A) Many congested vessels are present in the lamina propria. (B) Vessels exhibit a thin muscular coat. (C) Valve leaflets are present.

  

  Venous malformation. (A) Venules of varying sizes fill the superficial and deep lamina propria. (B) Venules exhibit varying thickness of muscle wall. (C) Thin muscle coat is present around most vessels (trichrome stain).

Differential Diagnosis

• •

  Arteriovenous malformations exhibit the presence of arterioles, arteries, veins, and venules; these lesions have high flow and distinct ultrasonographic findings.

• •

  Telangiectasia seen in limited systemic sclerosis (previously known as calcinosis-Raynaud phenomenon-esophageal dysmotility-sclerodactyly-telangiectasia [CREST] syndrome), an autoimmune condition characterized by anticentromere antibodies, and hereditary hemorrhagic telangiectasia, an autosomal dominant vascular dysplasia with HHT-1 , HHT-2, or SMAD4 mutations, consist of numerous dilated vessels in the lamina propria of the tongue or lips.

Management and Prognosis

• •

  Excision is the treatment of choice for varices and small venous malformations; laser ablation and sclerotherapy are useful treatments for larger lesions.

Clinical Findings

• •

  The mean age of occurrence is in the sixth decade with equal gender distribution; there is a bluish, sometimes nodular, often vermiform, pulsatile lesion of the lip, with the lower lip involved twice as frequently; clinically it is often mistaken for mucocele.

Etiopathogenesis and Histopathologic Features

Caliber-persistent labial artery represents a branch of the labial artery that fails to reduce its caliber even in the superficial tissues.

• •

  A normal artery with elastic lamina and thick muscular wall lies within the lamina propria, with an artery diameter-to-depth ratio of less than 1.6 ( Fig. 6.14 ).

  

  Caliber-persistent labial artery. (A) An artery is present in the deep lamina propria. (B) Artery with elastic lamina and thick muscle coat. (C) Elastin stain outlines the elastic lamina.

Management and Prognosis

• •

  Trauma leads to pulsatile bleeding, and the biopsy is diagnostic; ultrasonographic imaging mitigates the need for a biopsy, but this is rarely performed because the clinical impression is usually that of mucocele, which is normally excised.

Clinical Findings

• •

  This occurs in children, teenagers, and young adults as clusters of translucent vesicular structures resembling “frog spawn,” with at least 50% of cases occurring on the tongue ( Fig. 6.15 ); congenital lesions occur on the alveolar ridge in neonates (see Chapter 2 ).

  

  Lymphatic malformation of the tongue manifesting as clusters of hemorrhagic and ulcerated vesicles.

  (Courtesy Dr. Bonnie Padwa, Harvard School of Dental Medicine, Boston, MA.)

Etiopathogenesis and Histopathologic Features

Mutations in PIK3CA have been identified in extraoral lymphatic malformations and in sporadic syndromes associated with such malformative/overgrowth disorders (eg Klippel-Trenaunay syndrome), although it is unclear how such mutations that arise during embryogenesis produce these malformations.

• •

  Dilated vascular spaces are lined by a single layer of endothelial cells (that are usually D2-40 [podoplanin]+) often with valve leaflets, and are filled with pale, wispy, or denser eosinophilic material; these typically abut the epithelium, which has a bosselated surface, and vascular channels may insinuate into the underlying muscle ( Fig. 6.16 ); sometimes dilated venous channels are also present.

  

  Lymphangioma circumscriptum. (A) Circumscribed collection of large vascular spaces within the superficial and deep lamina propria. (B) Vascular spaces abut the epithelium. (C) Vascular spaces are lined by a single layer of endothelial cells and filled with pale, wispy lymph. (D) Lymphatic endothelium showing cytoplasmic positivity for D2-40.

Differential Diagnosis

• •

  Vessels of venous malformations have thin muscular coats and usually do not abut the epithelium.

Management and Prognosis

• •

  Excision or laser ablation is curative for small lesions, and embolization with debulking is the treatment for large lesions.

Clinical Findings

This occurs in the third to fifth decade and is twice as common in males; it presents as a painless nodule with 90% occurring on the lips (the most common site), tongue or buccal mucosa, sometimes with a history of trauma.

Etiopathogenesis and Histopathologic Features

FOS gene rearrangement has been noted in only 5% of head and neck cases with the angiolymphoid hyperplasia pattern, and 43% and 59% in lesions in the extremities and bone, respectively. It may be that the head and neck cases with the angiolymphoid hyperplasia pattern may represent a reactive rather than neoplastic process associated with vascular injury as compared with classic and cellular types of epithelioid hemangioma.

Classic lesions exhibit a circumscribed, multilobular proliferation of capillaries and small vessels surrounding a larger damaged vessel; endothelial cells are plump, epithelioid, and contain abundant amphophilic cytoplasm, sometimes with an intracytoplasmic vacuole representing a rudimentary lumen; nuclei have dispersed chromatin and small nucleoli.

• •

  There is a moderate to marked lymphocytic infiltrate and variable number of eosinophils ( Fig. 6.17 ). There may be outward maturation with nests of epithelioid cells in the center, small-lumen vessels further out, and well-formed vessels at the periphery.

  

  Epithelioid hemangioma. (A) Circumscribed multilobular cellular nodule with dilated large vessels in the center. (B) Many capillaries, epithelioid cells, and lymphocytes. (C) Epithelioid endothelial cells with large nuclei. (D) Cells show cytoplasmic positivity for CD31.

• •

  Endothelial cells are positive for factor VIII–related antigen, CD31, CD34, and glucose transporter-1 (GLUT-1), and are negative for S100 protein.

Differential Diagnosis

• •

  Kimura disease affects Asian men in the third and fourth decades and presents as nodules within the subcutaneous tissues of the head and neck, enlarged lymph nodes, or enlarged parotid gland; there is a patchy lymphocytic infiltrate with many germinal centers and eosinophils ( Fig. 6.18 ).

  

  Kimura disease. (A) Fibrosis and a dense lymphocytic infiltrate with many germinal centers. (B) Germinal center, many lymphocytes, plasma cells, and eosinophils.

• •

  Epithelioid hemangioendothelioma consists of strands and cords of epithelioid and slightly atypical endothelial cells with abundant eosinophilic cytoplasm, prominent cytoplasmic vacuoles, and myxochondroid or hyaline stroma; well-formed vascular channels are usually absent.

• •

  Epithelioid angiosarcoma consists of sheets of epithelioid cells with significant cytologic atypia and hyperchromasia.

Management and Prognosis

• •

  Excision is curative.

Clinical Findings

There are four clinical presentations:

• •

  Classic indolent type that involves the skin of the lower legs and sometimes the oral mucosa and viscera in older men of Mediterranean or Jewish descent.

• •

  African endemic type that occurs in adults and children and involves the skin of the lower legs and lymph nodes, and tends to be progressive with the lymphadenopathic type being aggressive.

• •

  Iatrogenic type that is associated with immunosuppression (especially after renal and lung transplantation) with localized or disseminated mucocutaneous lesions and sometimes visceral involvement; lesions may regress on reduction of immunosuppression.

• •

  Epidemic type that is found in patients with HIV/AIDS with disseminated mucocutaneous lesions and sometimes visceral involvement; lesions may flare with antiretroviral therapy; this coexists with the endemic form in Africa; Kaposi sarcoma is an AIDS-defining illness.

• •

  Lesions go through stages as follows: dusky red or purple macule (early patch stage), plaque (plaque stage), or nodular mass (tumor stage); the most common sites are maxillary gingiva, palatal mucosa, or tongue; infiltration of bone resulting in loosening of teeth ( Fig. 6.19 ); oral involvement is seen in only 2% to 5% of nonepidemic cases and in 60% to 70% of patients with HIV/AIDS.

  

  AIDS-associated Kaposi sarcoma. (A) Maxillary gingiva. (B) Tongue dorsum.

• •

  Up to 60% of subjects who are seropositive for HHV-8 excrete this virus in saliva.

• •

  Worsening of Kaposi sarcoma is one of the features of patients on antiretroviral therapy who develop immune reconstitution inflammatory syndrome (IRIS).

Etiopathogenesis and Histopathologic Features

Activity of Kaposi sarcoma-associated herpesvirus or HHV-8 infects and reprograms circulating mononuclear and endothelial “progenitor cells” to resemble lymphatic endothelium and to express D2-40 (podoplanin), and vascular endothelial growth factor receptor (VEGFR-3); there is also upregulation of HHV-8 gene products such as latency-associated nuclear antigen-1 (LANA-1); transmission may be through saliva rather than through blood or semen. However, not all patients who have been infected with HHV-8 develop Kaposi sarcoma.

• •

  Most oral cavity cases are in the nodular stage and consist of a cellular proliferation of spindle cells in fascicles with slitlike vascular spaces, and abundant extravascular erythrocytes, hemosiderin and intra- and extracytoplasmic periodic acid–Schiff (PAS)-positive eosinophilic globules; nuclei are spindled with slight variation in size, dispersed chromatin, and small nucleoli; mitotic activity may be noted ( Figs. 6.20 and 6.21A ).

  

  Kaposi sarcoma. (A) Cellular proliferation of spindle cells with dilated vascular spaces and abundant fresh hemorrhage. (B) Spindle cells surround slitlike spaces and show mild nuclear pleomorphism and mitotic activity; erythrocytes are present between spindle cells and within lumen.

  

  Kaposi sarcoma. (A) Plump spindle cells, eosinophilic globules, and abundant hemosiderin. (B) Positive immunostaining for nuclear HHV-8.

• •

  Histologic variants have been identified such as anaplastic, lymphangioma-like, telangiectatic, glomeruloid, keloidal, and hyperkeratotic, although rarely in the mouth.

• •

  Nuclear positivity for LANA-1 is diagnostic ( Fig. 6.21B ); spindle cells also exhibit cytoplasmic positivity for factor VIII–related antigen, CD31 (lower diagnostic sensitivity in tumor stage because it is removed by K5 protein produced by the virus), CD34, D2-40, PROX-1 and VEGFR-3, and also nuclear positivity for FLI-1 and BCL-2.

Differential Diagnosis

• •

  The differential diagnosis of Kaposi sarcoma is vast and includes benign and malignant vasoformative and nonvasoformative spindle cell tumors. The presence of vascular markers and LANA-1 is diagnostic.

Management and Prognosis

• •

  Oral lesions are successfully treated with excision, laser ablation, intralesional vinblastine therapy, and radiation; systemic therapy includes pegylated liposomal doxorubicin or daunorubicin; novel treatments include antiangiogenic agents such as bevacizumab, in addition to mammalian target of rapamycin (mTOR) inhibitors.

• •

  Reduction in immunosuppression in posttransplantation patients with iatrogenic Kaposi sarcoma may lead to regression of tumors.