Lesher Jl Jr

Intravenous immunoglobulin (IVIg) has been advocated as therapy for several immune-mediated and autoimmune skin disorders, and side effects such as vasomotor symptoms, anaphylactic reactions, and renal failure have been well documented.1 Thrombotic complications, such as stroke and myocardial infarction, also have been documented in the neurologic and cardiologic literature but have received little notice from dermatologists.2,3 One recent report in the dermatologic literature described 2 cases of thrombotic events, including a 65-year-old woman with pemphigus vulgaris who developed an upper extremity deep venous thrombosis (DVT) after receiving IVIg.4 We now report a case of thrombosis in the setting of IVIg therapy, only the fourth such case, to our knowledge, in the dermatology literature. We also review some less commonly known clinical presentations of thrombotic events associated with this therapy. 

Case Report

We were treating a 43-year-old black man who had an 18-month history of oral pemphigus vulgaris. His disease, which had been limited to the oral mucosa, had been refractory to numerous therapies including prednisone alone or with mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, and oral cyclophosphamide. His trial of cyclosporine was complicated by the development of hypertension, which necessitated oral antihypertensive medication.

After much consideration and investigation into the literature supporting the use of IVIg in refractory pemphigus vulgaris,5,6 we decided to proceed with this therapy. In the first treatment session, the patient received IVIg 40 g daily for 5 consecutive days. He experienced mild chills but otherwise tolerated the therapy well. However, no clinical benefit was observed. After further evaluation of the literature on the benefit of repeated doses of IVIg, we elected to repeat the therapy, this time using a regimen advocated by Ahmed's group.7 In the second course, which was begun 3 months after the first course, the patient received IVIg 70 g daily for 3 consecutive days, for a total dose of 2 g/kg. A complete blood count and metabolic panel on the last day of the infusion were within reference range. The patient had no notable clinical benefit after the second course of IVIg therapy.

Sixteen days after his last IVIg treatment, the patient underwent elective surgery at a local hospital for an anal fissure. The patient noted that he was particularly lethargic for the 3 days of his hospital stay, but he resumed his normal active daily routine immediately after discharge. Twenty-six days after his last IVIg treatment and 10 days after his anal surgery, he noted significant swelling and pain in his left calf that progressed over the course of several days. Thirty days after his last therapy, he was admitted to the hospital for workup of his leg swelling. A Doppler study demonstrated thrombus in the superficial femoral vein, common femoral vein, and popliteal vein. A diagnosis of DVT was made, and the patient was discharged on a therapeutic regimen of warfarin.

Comment

To our knowledge, there are only 3 reports in the dermatologic literature regarding thrombotic complications in the setting of IVIg therapy. Katz et al4 described one patient with pemphigus vulgaris who developed an upper extremity DVT and a 67-year-old woman with dermatomyositis who had a thromboembolic stroke. Bystryn et al6 also described a patient with pemphigus vulgaris who developed a mild stroke that had been attributed to hypertension.

A review of the literature regarding thrombotic complications with IVIg also revealed several other clinical scenarios of which dermatologists should be made aware. Evangelou et al8 reported a case of transverse sinus thrombosis presenting as an acute, sudden, severe headache in a 54-year-old woman who had recently received IVIg replacement therapy. Of note, the woman was known to have thrombocytosis prior to the therapy.8 In addition, Klaesson et al9 reported fatal venoocclusive disease of the liver in 11% of patients who had bone marrow transplants and were treated with IVIg; none of the transplant patients who served as controls experienced fatal venoocclusive disease of the liver. The difference was statistically significant (P=.02).9 Finally, Steinberger and Coleman10 reported a case of Anton syndrome in a patient with Guillain-Barre syndrome who was treated with IVIg. Anton syndrome is a form of cortical blindness in which the patient denies the visual impairment and may even attempt to ambulate, bumping into surrounding objects. This syndrome arises from damage to the occipital lobes, and the authors speculated that it arose in the setting of hyperviscosity, a known consequence of treatment with IVIg.10

Serial measurements of serum viscosity in patients with amyotrophic lateral sclerosis and polyneuropathy associated with IgM paraproteinemia before and after treatment with IVIg demonstrated an increase in serum viscosity, with the majority of patients having values above the upper limit of the reference range.11 In addition to the hyperviscosity created by IVIg, other possible ways IVIg can predispose patients to thrombotic complications are through vasoactive effects and generation of platelet-activating factor.12 Specifically, IVIg has been shown to cause hypotension in a rat model, and in vitro incubation of human neutrophils with IVIg has elicited generation of platelet-activating factor.12

There are many known risk factors for thrombosis including immobility, obesity, surgery, trauma, pregnancy, oral contraceptive use, malignancy, and coagulation disorders. We believe our patient's DVT can be attributed at least in part to his IVIg therapy, though certainly his 3-day period of immobility after his anal fissure surgery, along with hypertension, could have been contributing factors. Other authors have noted that periods of immobility may have predisposed their patients to thrombosis after treatment with IVIg.13

Estimates regarding the absolute risk for thrombotic complications with IVIg therapy have ranged from 3% to 5%, although this has not been well-studied.11,14 At our institution, approximately 200 individuals received a total dose of 18,000 g of IVIg in 2003. Unfortunately, no mechanism is in place to record the frequency of complications. Certainly, more information is required to ascertain the overall frequency of clotting complications after IVIg.

Given the preponderance of evidence (including one controlled study) supporting a role for IVIg in causing thrombotic events, we believe physicians should consider traditional risk factors for thrombosis, particularly surgery and immobility, as possible contraindications to treatment with IVIg. There may be some benefit in performing a workup for more subtle predispositions for thrombosis such as factor V Leiden, protein C deficiency, or protein S deficiency. Additionally, if a patient has had a thrombotic complication while being treated with IVIg, caution should be exercised before reinstating therapy.

Emerson et al15 recently reported a case involving a 33-year-old woman who had DVT while being treated with IVIg for autoimmune thrombocytopenia and Coombs-positive hemolytic anemia. Five months after the DVT, IVIg therapy was reinstated, and the patient died from a pulmonary embolism. Further studies may be needed to determine if prophylactic anticoagulation with heparin or warfarin may be needed when IVIg is used in the setting of risk factors for thrombosis. 

Conclusion

We report the fourth case of thrombotic complications occurring with IVIg in the treatment of dermatologic diseases, and we maintain that caution should be exercised in employing this treatment modality in patients who have underlying risk factors for thrombotic events. In particular, caution should be used with immobile patients and with those who need to undergo surgery or other procedures that may render them susceptible to DVT. We reported this case to the US Food and Drug Administration Adverse Event Reporting System, and we encourage others to do the same if thrombotic complications with IVIg are encountered. 

Intravenous immunoglobulin (IVIg) has been advocated as therapy for several immune-mediated and autoimmune skin disorders, and side effects such as vasomotor symptoms, anaphylactic reactions, and renal failure have been well documented.1 Thrombotic complications, such as stroke and myocardial infarction, also have been documented in the neurologic and cardiologic literature but have received little notice from dermatologists.2,3 One recent report in the dermatologic literature described 2 cases of thrombotic events, including a 65-year-old woman with pemphigus vulgaris who developed an upper extremity deep venous thrombosis (DVT) after receiving IVIg.4 We now report a case of thrombosis in the setting of IVIg therapy, only the fourth such case, to our knowledge, in the dermatology literature. We also review some less commonly known clinical presentations of thrombotic events associated with this therapy. 

Case Report

We were treating a 43-year-old black man who had an 18-month history of oral pemphigus vulgaris. His disease, which had been limited to the oral mucosa, had been refractory to numerous therapies including prednisone alone or with mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, and oral cyclophosphamide. His trial of cyclosporine was complicated by the development of hypertension, which necessitated oral antihypertensive medication.

After much consideration and investigation into the literature supporting the use of IVIg in refractory pemphigus vulgaris,5,6 we decided to proceed with this therapy. In the first treatment session, the patient received IVIg 40 g daily for 5 consecutive days. He experienced mild chills but otherwise tolerated the therapy well. However, no clinical benefit was observed. After further evaluation of the literature on the benefit of repeated doses of IVIg, we elected to repeat the therapy, this time using a regimen advocated by Ahmed's group.7 In the second course, which was begun 3 months after the first course, the patient received IVIg 70 g daily for 3 consecutive days, for a total dose of 2 g/kg. A complete blood count and metabolic panel on the last day of the infusion were within reference range. The patient had no notable clinical benefit after the second course of IVIg therapy.

Sixteen days after his last IVIg treatment, the patient underwent elective surgery at a local hospital for an anal fissure. The patient noted that he was particularly lethargic for the 3 days of his hospital stay, but he resumed his normal active daily routine immediately after discharge. Twenty-six days after his last IVIg treatment and 10 days after his anal surgery, he noted significant swelling and pain in his left calf that progressed over the course of several days. Thirty days after his last therapy, he was admitted to the hospital for workup of his leg swelling. A Doppler study demonstrated thrombus in the superficial femoral vein, common femoral vein, and popliteal vein. A diagnosis of DVT was made, and the patient was discharged on a therapeutic regimen of warfarin.

Comment

To our knowledge, there are only 3 reports in the dermatologic literature regarding thrombotic complications in the setting of IVIg therapy. Katz et al4 described one patient with pemphigus vulgaris who developed an upper extremity DVT and a 67-year-old woman with dermatomyositis who had a thromboembolic stroke. Bystryn et al6 also described a patient with pemphigus vulgaris who developed a mild stroke that had been attributed to hypertension.

A review of the literature regarding thrombotic complications with IVIg also revealed several other clinical scenarios of which dermatologists should be made aware. Evangelou et al8 reported a case of transverse sinus thrombosis presenting as an acute, sudden, severe headache in a 54-year-old woman who had recently received IVIg replacement therapy. Of note, the woman was known to have thrombocytosis prior to the therapy.8 In addition, Klaesson et al9 reported fatal venoocclusive disease of the liver in 11% of patients who had bone marrow transplants and were treated with IVIg; none of the transplant patients who served as controls experienced fatal venoocclusive disease of the liver. The difference was statistically significant (P=.02).9 Finally, Steinberger and Coleman10 reported a case of Anton syndrome in a patient with Guillain-Barre syndrome who was treated with IVIg. Anton syndrome is a form of cortical blindness in which the patient denies the visual impairment and may even attempt to ambulate, bumping into surrounding objects. This syndrome arises from damage to the occipital lobes, and the authors speculated that it arose in the setting of hyperviscosity, a known consequence of treatment with IVIg.10

Serial measurements of serum viscosity in patients with amyotrophic lateral sclerosis and polyneuropathy associated with IgM paraproteinemia before and after treatment with IVIg demonstrated an increase in serum viscosity, with the majority of patients having values above the upper limit of the reference range.11 In addition to the hyperviscosity created by IVIg, other possible ways IVIg can predispose patients to thrombotic complications are through vasoactive effects and generation of platelet-activating factor.12 Specifically, IVIg has been shown to cause hypotension in a rat model, and in vitro incubation of human neutrophils with IVIg has elicited generation of platelet-activating factor.12

There are many known risk factors for thrombosis including immobility, obesity, surgery, trauma, pregnancy, oral contraceptive use, malignancy, and coagulation disorders. We believe our patient's DVT can be attributed at least in part to his IVIg therapy, though certainly his 3-day period of immobility after his anal fissure surgery, along with hypertension, could have been contributing factors. Other authors have noted that periods of immobility may have predisposed their patients to thrombosis after treatment with IVIg.13

Estimates regarding the absolute risk for thrombotic complications with IVIg therapy have ranged from 3% to 5%, although this has not been well-studied.11,14 At our institution, approximately 200 individuals received a total dose of 18,000 g of IVIg in 2003. Unfortunately, no mechanism is in place to record the frequency of complications. Certainly, more information is required to ascertain the overall frequency of clotting complications after IVIg.

Given the preponderance of evidence (including one controlled study) supporting a role for IVIg in causing thrombotic events, we believe physicians should consider traditional risk factors for thrombosis, particularly surgery and immobility, as possible contraindications to treatment with IVIg. There may be some benefit in performing a workup for more subtle predispositions for thrombosis such as factor V Leiden, protein C deficiency, or protein S deficiency. Additionally, if a patient has had a thrombotic complication while being treated with IVIg, caution should be exercised before reinstating therapy.

Emerson et al15 recently reported a case involving a 33-year-old woman who had DVT while being treated with IVIg for autoimmune thrombocytopenia and Coombs-positive hemolytic anemia. Five months after the DVT, IVIg therapy was reinstated, and the patient died from a pulmonary embolism. Further studies may be needed to determine if prophylactic anticoagulation with heparin or warfarin may be needed when IVIg is used in the setting of risk factors for thrombosis. 

Conclusion

We report the fourth case of thrombotic complications occurring with IVIg in the treatment of dermatologic diseases, and we maintain that caution should be exercised in employing this treatment modality in patients who have underlying risk factors for thrombotic events. In particular, caution should be used with immobile patients and with those who need to undergo surgery or other procedures that may render them susceptible to DVT. We reported this case to the US Food and Drug Administration Adverse Event Reporting System, and we encourage others to do the same if thrombotic complications with IVIg are encountered. 

Intravenous immunoglobulin (IVIg) has been advocated as therapy for several immune-mediated and autoimmune skin disorders, and side effects such as vasomotor symptoms, anaphylactic reactions, and renal failure have been well documented.1 Thrombotic complications, such as stroke and myocardial infarction, also have been documented in the neurologic and cardiologic literature but have received little notice from dermatologists.2,3 One recent report in the dermatologic literature described 2 cases of thrombotic events, including a 65-year-old woman with pemphigus vulgaris who developed an upper extremity deep venous thrombosis (DVT) after receiving IVIg.4 We now report a case of thrombosis in the setting of IVIg therapy, only the fourth such case, to our knowledge, in the dermatology literature. We also review some less commonly known clinical presentations of thrombotic events associated with this therapy. 

Case Report

We were treating a 43-year-old black man who had an 18-month history of oral pemphigus vulgaris. His disease, which had been limited to the oral mucosa, had been refractory to numerous therapies including prednisone alone or with mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, and oral cyclophosphamide. His trial of cyclosporine was complicated by the development of hypertension, which necessitated oral antihypertensive medication.

After much consideration and investigation into the literature supporting the use of IVIg in refractory pemphigus vulgaris,5,6 we decided to proceed with this therapy. In the first treatment session, the patient received IVIg 40 g daily for 5 consecutive days. He experienced mild chills but otherwise tolerated the therapy well. However, no clinical benefit was observed. After further evaluation of the literature on the benefit of repeated doses of IVIg, we elected to repeat the therapy, this time using a regimen advocated by Ahmed's group.7 In the second course, which was begun 3 months after the first course, the patient received IVIg 70 g daily for 3 consecutive days, for a total dose of 2 g/kg. A complete blood count and metabolic panel on the last day of the infusion were within reference range. The patient had no notable clinical benefit after the second course of IVIg therapy.

Sixteen days after his last IVIg treatment, the patient underwent elective surgery at a local hospital for an anal fissure. The patient noted that he was particularly lethargic for the 3 days of his hospital stay, but he resumed his normal active daily routine immediately after discharge. Twenty-six days after his last IVIg treatment and 10 days after his anal surgery, he noted significant swelling and pain in his left calf that progressed over the course of several days. Thirty days after his last therapy, he was admitted to the hospital for workup of his leg swelling. A Doppler study demonstrated thrombus in the superficial femoral vein, common femoral vein, and popliteal vein. A diagnosis of DVT was made, and the patient was discharged on a therapeutic regimen of warfarin.

Comment

To our knowledge, there are only 3 reports in the dermatologic literature regarding thrombotic complications in the setting of IVIg therapy. Katz et al4 described one patient with pemphigus vulgaris who developed an upper extremity DVT and a 67-year-old woman with dermatomyositis who had a thromboembolic stroke. Bystryn et al6 also described a patient with pemphigus vulgaris who developed a mild stroke that had been attributed to hypertension.

A review of the literature regarding thrombotic complications with IVIg also revealed several other clinical scenarios of which dermatologists should be made aware. Evangelou et al8 reported a case of transverse sinus thrombosis presenting as an acute, sudden, severe headache in a 54-year-old woman who had recently received IVIg replacement therapy. Of note, the woman was known to have thrombocytosis prior to the therapy.8 In addition, Klaesson et al9 reported fatal venoocclusive disease of the liver in 11% of patients who had bone marrow transplants and were treated with IVIg; none of the transplant patients who served as controls experienced fatal venoocclusive disease of the liver. The difference was statistically significant (P=.02).9 Finally, Steinberger and Coleman10 reported a case of Anton syndrome in a patient with Guillain-Barre syndrome who was treated with IVIg. Anton syndrome is a form of cortical blindness in which the patient denies the visual impairment and may even attempt to ambulate, bumping into surrounding objects. This syndrome arises from damage to the occipital lobes, and the authors speculated that it arose in the setting of hyperviscosity, a known consequence of treatment with IVIg.10

Serial measurements of serum viscosity in patients with amyotrophic lateral sclerosis and polyneuropathy associated with IgM paraproteinemia before and after treatment with IVIg demonstrated an increase in serum viscosity, with the majority of patients having values above the upper limit of the reference range.11 In addition to the hyperviscosity created by IVIg, other possible ways IVIg can predispose patients to thrombotic complications are through vasoactive effects and generation of platelet-activating factor.12 Specifically, IVIg has been shown to cause hypotension in a rat model, and in vitro incubation of human neutrophils with IVIg has elicited generation of platelet-activating factor.12

There are many known risk factors for thrombosis including immobility, obesity, surgery, trauma, pregnancy, oral contraceptive use, malignancy, and coagulation disorders. We believe our patient's DVT can be attributed at least in part to his IVIg therapy, though certainly his 3-day period of immobility after his anal fissure surgery, along with hypertension, could have been contributing factors. Other authors have noted that periods of immobility may have predisposed their patients to thrombosis after treatment with IVIg.13

Estimates regarding the absolute risk for thrombotic complications with IVIg therapy have ranged from 3% to 5%, although this has not been well-studied.11,14 At our institution, approximately 200 individuals received a total dose of 18,000 g of IVIg in 2003. Unfortunately, no mechanism is in place to record the frequency of complications. Certainly, more information is required to ascertain the overall frequency of clotting complications after IVIg.

Given the preponderance of evidence (including one controlled study) supporting a role for IVIg in causing thrombotic events, we believe physicians should consider traditional risk factors for thrombosis, particularly surgery and immobility, as possible contraindications to treatment with IVIg. There may be some benefit in performing a workup for more subtle predispositions for thrombosis such as factor V Leiden, protein C deficiency, or protein S deficiency. Additionally, if a patient has had a thrombotic complication while being treated with IVIg, caution should be exercised before reinstating therapy.

Emerson et al15 recently reported a case involving a 33-year-old woman who had DVT while being treated with IVIg for autoimmune thrombocytopenia and Coombs-positive hemolytic anemia. Five months after the DVT, IVIg therapy was reinstated, and the patient died from a pulmonary embolism. Further studies may be needed to determine if prophylactic anticoagulation with heparin or warfarin may be needed when IVIg is used in the setting of risk factors for thrombosis. 

Conclusion

We report the fourth case of thrombotic complications occurring with IVIg in the treatment of dermatologic diseases, and we maintain that caution should be exercised in employing this treatment modality in patients who have underlying risk factors for thrombotic events. In particular, caution should be used with immobile patients and with those who need to undergo surgery or other procedures that may render them susceptible to DVT. We reported this case to the US Food and Drug Administration Adverse Event Reporting System, and we encourage others to do the same if thrombotic complications with IVIg are encountered. 

Pyogenic granuloma, often referred to by many other names, including lobular capillary hemangioma, is a benign vascular hyperplasia that tends to occur on the gingiva, lips, nasal mucosa, face, and hands.1,2 The lesion often is preceded by minor trauma, has a history of bleeding easily, and appears as a pedunculated or sessile papule with a rough red surface. There is a well-known tendency toward local recurrence after treatment.3 Results of a histopathologic examination shows lobular aggregates of capillaries and venules with plump endothelial cells.4 The pathogenesis of this lesion is poorly understood.

Port-wine stains are a type of nevus flammeus that present as a deep red or purple macule and are typically unilateral.4 Unlike salmon patches, the other type of nevus flammeus, port-wine stains tend to persist into adulthood.5 These congenital malformations are composed of capillary and venule ectasia in the dermis, and the ectasias progress over the course of a lifetime with increasing erythrocyte stasis.6-8 As Finley6 pointed out, in time, the port-wine stain can develop a thickened "cobblestone pattern," as well as nodules that are thought to be arteriovenous malformations or "localized tumor formations." Klapman and Yao8 recently noted that the thickening and nodules are most likely to occur in the areas of the face innervated by the second and third branches of the trigeminal nerve than in other parts of the body. Port-wine stains have been associated with other abnormalities such as nevus anemicus, glaucoma, choroidal angiomas, and Sturge-Weber syndrome.4 The pathogenesis of the port-wine stain has been a controversial issue, but one possibility is that it represents a deficiency of sympathetic innervation of blood vessels.4

The occurrence of vascular neoplasms arising in capillary malformations is a rare, but documented, event.9 Pyogenic granulomas infrequently have been reported to occur in association with other vascular abnormalities such as port-wine stains or hemangiomas, particularly after laser treatment.10,11 A number of other vascular neoplasms, such as capillary hemangiomas, tufted angiomas, and cavernous hemangiomas, have been reported in association with port-wine stains, as well.6,12,13 Very few pyogenic granulomas have arisen in port-wine stains without a history of trauma, laser treatment, or pregnancy. We now report a pyogenic granuloma occurring within a port-wine stain without a history of trauma or laser treatment in a man, and we contend that this occurrence offers unique insight into the pathogenesis of these poorly understood but commonly encountered entities. 

Case Report

A 35-year-old Asian man with a history of a port-wine stain on his left upper back presented for evaluation of a "mushroom" growing within his birthmark (Figure 1). He noted that some lesion had been present in this location for several months but that it had grown rapidly in the previous 3 weeks and begun to bleed easily. There was no history of trauma or treatment of the area. On physical examination, the patient had a 1.4-cm pedunculated, moist tumor with a rough surface within a port-wine stain with surrounding contact dermatitis from the bandaging he had used to protect the friable papule. Saucerization was performed, and the extremely vascularized base was cauterized. Results of histopathologic examination revealed lobules of vascular hyperplasia consistent with pyogenic granuloma (Figure 2). Vascular ectasia was seen below the pyogenic granuloma that represented the underling port-wine stain.

Comment

The Table documents the reported cases of pyogenic granulomas arising within port-wine stains.3,10,11,13-23 Many have occurred after laser treatment of port-wine stains.11,15-17,24,25 Several cases have occurred after other manipulation of port-wine stains, such as grenz-ray therapy15 or local trauma.20 Three cases occurred during pregnancy, which is a hormonal state that is known to predispose the patient to the formation of pyogenic granulomas, including one patient who previously was treated with the 577-nm pulsed dye laser and subsequently became pregnant.14,15,21 Holloway et al18 noted the development of a proliferation that had a superficial component of pyogenic granuloma and a deeper component of cavernous hemangioma. Other authors have seen the occasional association of port-wine stains and cavernous hemangiomas.6 Not surprisingly, pyogenic granulomas have occurred within port-wine stains in the setting of other syndromes, such as phacomatosis pigmentovascularis and Sturge-Weber syndrome.19

Only rarely does the pyogenic granuloma seem to emerge from the port-wine stain without a history of manipulation or pregnancy, as it did in the present case. When there is no history of predisposing factors, the presentation can be very alarming, simulating other processes such as amelanotic melanoma.22,23 Interestingly, as opposed to the thickening and nodules that have shown to be more likely to develop in port-wine stains in the distribution of the trigeminal nerve, most of the pyogenic granulomas that have arisen in port-wine stains did so outside of this distribution, occurring more often on the neck, trunk, or extremities.

Clearly, the co-occurrence of these 2 vascular abnormalities must offer some information on the pathogenesis of these poorly understood conditions. Several years ago, Swerlick and Cooper10 speculated that the co-occurrence supported the possibility of pyogenic granulomas developing at the sites of microscopic arteriovenous anastomoses. More recently, as discussed by Garzon et al,9 a number of studies indicate that abnormalities in embryonic vasculogenesis are involved in forming vascular malformations such as port-wine stains, and these same abnormalities may predispose patients toward forming vascular hyperplasia or tumors. The well-known hormonally driven vascular changes that happen during pregnancy also may be able to generate pyogenic granulomas in the setting of port-wine stains.21

On a basic science level, chemical mediators such as inducible nitric oxide synthase have been implicated in the formation of pyogenic granulomas, and mast cells have been found to be dramatically increased in the settings of both pyogenic granulomas and port-wine stains, though this may not be evidence of a cause-and-effect relationship.26,27 With regard to laser-induced pyogenic granulomas in port-wine stains, speculation has involved several factors including local tissue trauma in an area of increased microscopic arteriovenous anastomoses, retention of abnormal vasculature, and nonspecific laser interaction with tissue.15,16

Pyogenic granulomas tend to develop on the fingers, lips, face, and hands (places known to be rich in arteriovenous anastomoses), suggesting that this vascular phenomenon tends to occur with minor trauma in the setting of such anastomoses.13,20 This conclusion is consistent with the available data. The present case of a pyogenic granuloma arising without recognized trauma in a port-wine stain also supports this hypothesis.

Conclusion

Pyogenic granuloma is a well-known and probably underreported complication of port-wine stains. Unlike thickening and nodule formation that tend to occur in port-wine stains in the trigeminal nerve distribution, pyogenic granulomas arising in port-wine stains tend to occur more commonly on the neck, trunk, or extremities. The pyogenic granuloma should not be confused with a true malignancy because it represents hyperplasia of vascular tissue in response to trauma, but the performance of an excisional biopsy is warranted.

Pyogenic granuloma, often referred to by many other names, including lobular capillary hemangioma, is a benign vascular hyperplasia that tends to occur on the gingiva, lips, nasal mucosa, face, and hands.1,2 The lesion often is preceded by minor trauma, has a history of bleeding easily, and appears as a pedunculated or sessile papule with a rough red surface. There is a well-known tendency toward local recurrence after treatment.3 Results of a histopathologic examination shows lobular aggregates of capillaries and venules with plump endothelial cells.4 The pathogenesis of this lesion is poorly understood.

Port-wine stains are a type of nevus flammeus that present as a deep red or purple macule and are typically unilateral.4 Unlike salmon patches, the other type of nevus flammeus, port-wine stains tend to persist into adulthood.5 These congenital malformations are composed of capillary and venule ectasia in the dermis, and the ectasias progress over the course of a lifetime with increasing erythrocyte stasis.6-8 As Finley6 pointed out, in time, the port-wine stain can develop a thickened "cobblestone pattern," as well as nodules that are thought to be arteriovenous malformations or "localized tumor formations." Klapman and Yao8 recently noted that the thickening and nodules are most likely to occur in the areas of the face innervated by the second and third branches of the trigeminal nerve than in other parts of the body. Port-wine stains have been associated with other abnormalities such as nevus anemicus, glaucoma, choroidal angiomas, and Sturge-Weber syndrome.4 The pathogenesis of the port-wine stain has been a controversial issue, but one possibility is that it represents a deficiency of sympathetic innervation of blood vessels.4

The occurrence of vascular neoplasms arising in capillary malformations is a rare, but documented, event.9 Pyogenic granulomas infrequently have been reported to occur in association with other vascular abnormalities such as port-wine stains or hemangiomas, particularly after laser treatment.10,11 A number of other vascular neoplasms, such as capillary hemangiomas, tufted angiomas, and cavernous hemangiomas, have been reported in association with port-wine stains, as well.6,12,13 Very few pyogenic granulomas have arisen in port-wine stains without a history of trauma, laser treatment, or pregnancy. We now report a pyogenic granuloma occurring within a port-wine stain without a history of trauma or laser treatment in a man, and we contend that this occurrence offers unique insight into the pathogenesis of these poorly understood but commonly encountered entities. 

Case Report

A 35-year-old Asian man with a history of a port-wine stain on his left upper back presented for evaluation of a "mushroom" growing within his birthmark (Figure 1). He noted that some lesion had been present in this location for several months but that it had grown rapidly in the previous 3 weeks and begun to bleed easily. There was no history of trauma or treatment of the area. On physical examination, the patient had a 1.4-cm pedunculated, moist tumor with a rough surface within a port-wine stain with surrounding contact dermatitis from the bandaging he had used to protect the friable papule. Saucerization was performed, and the extremely vascularized base was cauterized. Results of histopathologic examination revealed lobules of vascular hyperplasia consistent with pyogenic granuloma (Figure 2). Vascular ectasia was seen below the pyogenic granuloma that represented the underling port-wine stain.

Comment

The Table documents the reported cases of pyogenic granulomas arising within port-wine stains.3,10,11,13-23 Many have occurred after laser treatment of port-wine stains.11,15-17,24,25 Several cases have occurred after other manipulation of port-wine stains, such as grenz-ray therapy15 or local trauma.20 Three cases occurred during pregnancy, which is a hormonal state that is known to predispose the patient to the formation of pyogenic granulomas, including one patient who previously was treated with the 577-nm pulsed dye laser and subsequently became pregnant.14,15,21 Holloway et al18 noted the development of a proliferation that had a superficial component of pyogenic granuloma and a deeper component of cavernous hemangioma. Other authors have seen the occasional association of port-wine stains and cavernous hemangiomas.6 Not surprisingly, pyogenic granulomas have occurred within port-wine stains in the setting of other syndromes, such as phacomatosis pigmentovascularis and Sturge-Weber syndrome.19

Only rarely does the pyogenic granuloma seem to emerge from the port-wine stain without a history of manipulation or pregnancy, as it did in the present case. When there is no history of predisposing factors, the presentation can be very alarming, simulating other processes such as amelanotic melanoma.22,23 Interestingly, as opposed to the thickening and nodules that have shown to be more likely to develop in port-wine stains in the distribution of the trigeminal nerve, most of the pyogenic granulomas that have arisen in port-wine stains did so outside of this distribution, occurring more often on the neck, trunk, or extremities.

Clearly, the co-occurrence of these 2 vascular abnormalities must offer some information on the pathogenesis of these poorly understood conditions. Several years ago, Swerlick and Cooper10 speculated that the co-occurrence supported the possibility of pyogenic granulomas developing at the sites of microscopic arteriovenous anastomoses. More recently, as discussed by Garzon et al,9 a number of studies indicate that abnormalities in embryonic vasculogenesis are involved in forming vascular malformations such as port-wine stains, and these same abnormalities may predispose patients toward forming vascular hyperplasia or tumors. The well-known hormonally driven vascular changes that happen during pregnancy also may be able to generate pyogenic granulomas in the setting of port-wine stains.21

On a basic science level, chemical mediators such as inducible nitric oxide synthase have been implicated in the formation of pyogenic granulomas, and mast cells have been found to be dramatically increased in the settings of both pyogenic granulomas and port-wine stains, though this may not be evidence of a cause-and-effect relationship.26,27 With regard to laser-induced pyogenic granulomas in port-wine stains, speculation has involved several factors including local tissue trauma in an area of increased microscopic arteriovenous anastomoses, retention of abnormal vasculature, and nonspecific laser interaction with tissue.15,16

Pyogenic granulomas tend to develop on the fingers, lips, face, and hands (places known to be rich in arteriovenous anastomoses), suggesting that this vascular phenomenon tends to occur with minor trauma in the setting of such anastomoses.13,20 This conclusion is consistent with the available data. The present case of a pyogenic granuloma arising without recognized trauma in a port-wine stain also supports this hypothesis.

Conclusion

Pyogenic granuloma is a well-known and probably underreported complication of port-wine stains. Unlike thickening and nodule formation that tend to occur in port-wine stains in the trigeminal nerve distribution, pyogenic granulomas arising in port-wine stains tend to occur more commonly on the neck, trunk, or extremities. The pyogenic granuloma should not be confused with a true malignancy because it represents hyperplasia of vascular tissue in response to trauma, but the performance of an excisional biopsy is warranted.

Pyogenic granuloma, often referred to by many other names, including lobular capillary hemangioma, is a benign vascular hyperplasia that tends to occur on the gingiva, lips, nasal mucosa, face, and hands.1,2 The lesion often is preceded by minor trauma, has a history of bleeding easily, and appears as a pedunculated or sessile papule with a rough red surface. There is a well-known tendency toward local recurrence after treatment.3 Results of a histopathologic examination shows lobular aggregates of capillaries and venules with plump endothelial cells.4 The pathogenesis of this lesion is poorly understood.

Port-wine stains are a type of nevus flammeus that present as a deep red or purple macule and are typically unilateral.4 Unlike salmon patches, the other type of nevus flammeus, port-wine stains tend to persist into adulthood.5 These congenital malformations are composed of capillary and venule ectasia in the dermis, and the ectasias progress over the course of a lifetime with increasing erythrocyte stasis.6-8 As Finley6 pointed out, in time, the port-wine stain can develop a thickened "cobblestone pattern," as well as nodules that are thought to be arteriovenous malformations or "localized tumor formations." Klapman and Yao8 recently noted that the thickening and nodules are most likely to occur in the areas of the face innervated by the second and third branches of the trigeminal nerve than in other parts of the body. Port-wine stains have been associated with other abnormalities such as nevus anemicus, glaucoma, choroidal angiomas, and Sturge-Weber syndrome.4 The pathogenesis of the port-wine stain has been a controversial issue, but one possibility is that it represents a deficiency of sympathetic innervation of blood vessels.4

The occurrence of vascular neoplasms arising in capillary malformations is a rare, but documented, event.9 Pyogenic granulomas infrequently have been reported to occur in association with other vascular abnormalities such as port-wine stains or hemangiomas, particularly after laser treatment.10,11 A number of other vascular neoplasms, such as capillary hemangiomas, tufted angiomas, and cavernous hemangiomas, have been reported in association with port-wine stains, as well.6,12,13 Very few pyogenic granulomas have arisen in port-wine stains without a history of trauma, laser treatment, or pregnancy. We now report a pyogenic granuloma occurring within a port-wine stain without a history of trauma or laser treatment in a man, and we contend that this occurrence offers unique insight into the pathogenesis of these poorly understood but commonly encountered entities. 

Case Report

A 35-year-old Asian man with a history of a port-wine stain on his left upper back presented for evaluation of a "mushroom" growing within his birthmark (Figure 1). He noted that some lesion had been present in this location for several months but that it had grown rapidly in the previous 3 weeks and begun to bleed easily. There was no history of trauma or treatment of the area. On physical examination, the patient had a 1.4-cm pedunculated, moist tumor with a rough surface within a port-wine stain with surrounding contact dermatitis from the bandaging he had used to protect the friable papule. Saucerization was performed, and the extremely vascularized base was cauterized. Results of histopathologic examination revealed lobules of vascular hyperplasia consistent with pyogenic granuloma (Figure 2). Vascular ectasia was seen below the pyogenic granuloma that represented the underling port-wine stain.

Comment

The Table documents the reported cases of pyogenic granulomas arising within port-wine stains.3,10,11,13-23 Many have occurred after laser treatment of port-wine stains.11,15-17,24,25 Several cases have occurred after other manipulation of port-wine stains, such as grenz-ray therapy15 or local trauma.20 Three cases occurred during pregnancy, which is a hormonal state that is known to predispose the patient to the formation of pyogenic granulomas, including one patient who previously was treated with the 577-nm pulsed dye laser and subsequently became pregnant.14,15,21 Holloway et al18 noted the development of a proliferation that had a superficial component of pyogenic granuloma and a deeper component of cavernous hemangioma. Other authors have seen the occasional association of port-wine stains and cavernous hemangiomas.6 Not surprisingly, pyogenic granulomas have occurred within port-wine stains in the setting of other syndromes, such as phacomatosis pigmentovascularis and Sturge-Weber syndrome.19

Only rarely does the pyogenic granuloma seem to emerge from the port-wine stain without a history of manipulation or pregnancy, as it did in the present case. When there is no history of predisposing factors, the presentation can be very alarming, simulating other processes such as amelanotic melanoma.22,23 Interestingly, as opposed to the thickening and nodules that have shown to be more likely to develop in port-wine stains in the distribution of the trigeminal nerve, most of the pyogenic granulomas that have arisen in port-wine stains did so outside of this distribution, occurring more often on the neck, trunk, or extremities.

Clearly, the co-occurrence of these 2 vascular abnormalities must offer some information on the pathogenesis of these poorly understood conditions. Several years ago, Swerlick and Cooper10 speculated that the co-occurrence supported the possibility of pyogenic granulomas developing at the sites of microscopic arteriovenous anastomoses. More recently, as discussed by Garzon et al,9 a number of studies indicate that abnormalities in embryonic vasculogenesis are involved in forming vascular malformations such as port-wine stains, and these same abnormalities may predispose patients toward forming vascular hyperplasia or tumors. The well-known hormonally driven vascular changes that happen during pregnancy also may be able to generate pyogenic granulomas in the setting of port-wine stains.21

On a basic science level, chemical mediators such as inducible nitric oxide synthase have been implicated in the formation of pyogenic granulomas, and mast cells have been found to be dramatically increased in the settings of both pyogenic granulomas and port-wine stains, though this may not be evidence of a cause-and-effect relationship.26,27 With regard to laser-induced pyogenic granulomas in port-wine stains, speculation has involved several factors including local tissue trauma in an area of increased microscopic arteriovenous anastomoses, retention of abnormal vasculature, and nonspecific laser interaction with tissue.15,16

Pyogenic granulomas tend to develop on the fingers, lips, face, and hands (places known to be rich in arteriovenous anastomoses), suggesting that this vascular phenomenon tends to occur with minor trauma in the setting of such anastomoses.13,20 This conclusion is consistent with the available data. The present case of a pyogenic granuloma arising without recognized trauma in a port-wine stain also supports this hypothesis.

Conclusion

Pyogenic granuloma is a well-known and probably underreported complication of port-wine stains. Unlike thickening and nodule formation that tend to occur in port-wine stains in the trigeminal nerve distribution, pyogenic granulomas arising in port-wine stains tend to occur more commonly on the neck, trunk, or extremities. The pyogenic granuloma should not be confused with a true malignancy because it represents hyperplasia of vascular tissue in response to trauma, but the performance of an excisional biopsy is warranted.