Sheehan DJ

Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous tumor of intermediate malignancy that is known to be locally aggressive.1 It is thought to be of fibrohistiocytic origin and accounts for 1% of all soft tissue malignancies.2 DFSP occurs in men and women with equal incidence, mostly on the trunk and less commonly on the proximal extremities, with a higher incidence in Caucasians. Most patients present between the second and fifth decades, though the disease can be noted in any age group and any anatomic location.3

Four clinical variants of early DFSP are thought to exist: confluent nodular lesions forming a sclerotic plaque, keloidlike sclerotic plaque, tumor, and atrophic plaque.4,5 The usual clinical appearance of DFSP at an early stage is as a slow-growing, asymptomatic plaque or nodule. The tumor's gross pathology is of a gray-white mass involving the dermis and subcutis; histologically, it is a poorly circumscribed infiltrative spindle cell tumor. The spindle cells, which are CD34+, are arranged in a storiform pattern described as a dense, poorly circumscribed, monomorphic cell proliferation arranged in fascicles that often reach and infiltrate the hypodermis.6,7 The 3 recognized histologic variants of DFSP are fibrosarcomatous, plaquelike, and myxoid forms.8 The infiltrating pattern accounts for the tumor's common recurrence after excision and the need for wide excision or Mohs micrographic surgery for curative removal.2,3,9-11 One recent review of atrophic DFSP implicated chromosomal translocations or the formation of supernumerary ring chromosomes in the pathogenesis of DFSP.12 These chromosomal events result in the fusion of the collagen type 1α1 gene with the platelet-derived growth factor-β chain gene. How this mutation could contribute to the atrophic phenotype is unknown.12 This review documents only 25 cases of atrophic DFSP in the literature. We present a case involving a woman who had an atrophic DFSP treated successfully with Mohs micrographic surgery and review 35 cases in the literature regarding this rare presentation of DFSP. 

Case Report

A 41-year-old white woman presented with a 12-year history of a well-demarcated, scalloped, markedly depressed, reddish brown, slightly firm, 4x5-cm plaque on the right chest (Figure 1). On initial evaluation, the patient denied prior trauma to the area or any past manipulation of the lesion. The patient's preoperative clinical differential diagnosis included atrophoderma of Pasini and Pierini, anetoderma, morphea, and lipoatrophy.

A punch biopsy of the lesion was performed. Results revealed a spindle cell neoplasm that was thought to be a dermatofibroma. The entire lesion was subsequently excised. Histopathology results of the excision specimen demonstrated atrophy of the dermis and a permeative spindle cell neoplasm with scattered multinucleated giant cells involving the dermis and underlying soft tissue with a few areas of a storiform growth pattern (Figure 2). The lesion also was diffusely immunoreactive for CD34 and extended to the margins of the specimen. A diagnosis of DFSP was made, and the patient was treated with Mohs micrographic surgery. Three stages of surgery were performed, and the final defect was 7.0x8.5 cm. The patient elected to allow the wound to heal by secondary intention. There was no evidence of recurrence 12 months after the procedure.

Comment

The atrophic presentation of DFSP is the rarest variant of this infrequent neoplasm. Although this subject was recently reviewed, there are several other important issues in the literature that need to be clarified regarding this unusual phenotype.12 For a lesion to be classified as atrophic, there should be both clinical and histologic evidence of atrophy. When the epidermis is atrophic, the result is shiny smooth skin clinically and flattening of the rete ridges histopathologically. Conversely, when the dermis or subcutaneous tissue is atrophic, the result is a loss in skin thickness and a corresponding loss of collagen bundles or subcutaneous fat histopathologically.13

Epidermal atrophy is commonly noted histologically in DFSP cases that present in the usual fashion.14,15 Only rarely has DFSP presented as a clinically depressed lesion.16-20 Even more rare is a documentation of dermal atrophy.12,21 We report a case of DFSP in which the initial lesion was an atrophic depression of the skin lacking nodularity and histologically demonstrating significant dermal atrophy.

A number of cases have been reported describing atrophic presentations of DFSP (Table 1).4,5,8,12,16-26 However, as Davis and Sanchez8 noted, rarely does a so-called atrophic DFSP present as a visible depression in the skin.16-21 Clearly, there is some discrepancy in the literature as to the nature of atrophy in relation to the clinical presentation of DFSP. Some authors have even speculated that the atrophic variant of DFSP is nothing more than an early presentation of the more usual DFSP prior to the formation of nodules.4 However, the fact that our patient had her lesion for 12 years prior to treatment without the formation of a nodular component indicates that the atrophic variant of DFSP is a real entity.

Table 2 demonstrates the sex and anatomic location of the patients in the 35 reported cases of DFSP described as atrophic or morpheaform, including the present case. The majority (20/35) of cases have been in female patients, and the most common location in both sexes has been the trunk (24/35). The next most common location was the lower extremity (7/35).

Table 3 documents the age and anatomic location of the 9 cases clinically described as resembling lipoatrophy, atrophoderma or anetoderma, or that were significantly clinically depressed based on clinical photographs, ie, the cases most similar to the one we now present.4,16,19-21,25 Three of the 9 cases were on the trunks of females aged 16 to 41 years. Interestingly, 4 of the remaining 6 cases were on the lower extremities of children aged 18 months to 16 years.

A number of conclusions can be drawn from this data. First, atrophic variants of DFSP tend to occur most often on the trunk, as do the usual variants of DFSP. However, the atrophic variants tend to occur more often in females as opposed to the standard presentation of DFSP, which occurs with equal frequency in males and females. In addition, a distinction exists in the presentation of atrophic lesions, which can have either a morpheaform or a more clinically depressed appearance, mimicking such disorders as anetoderma, atrophoderma, or lipoatrophy. We report such a case mimicking atrophoderma, and we contend that this is the rarest presentation of atrophic DFSP.

One final entity in the differential diagnosis of a depressed plaque on the trunk would be an atrophic dermatofibroma. The dermatofibroma, a well-known and benign cousin of DFSP, is often noted to have some dermal atrophy grossly with lateral pressure, described as a dimple sign.27 As Requena and Reichel28 pointed out, even when there is a central depression over a dermatofibroma without lateral pressure, no true loss of the dermis is seen histopathologically. As such, this central depression doesn't represent true dermal atrophy.28 However, the dermatofibroma also can present as a depressed lesion demonstrating thinning of the dermis histologically, and this variety of dermatofibroma has been described as atrophic.28-31 Although a recently published article recommended considering a diagnosis of atrophic dermatofibroma in the case of "atrophic, depressed lesions on the upper body of middle-aged women,"31 we would maintain that atrophic DFSP also should be considered in the differential diagnosis.

One possibility to clarify the imprecision in the literature in relation to the clinical presentation of DFSP would be to eliminate protuberans from the name, thereby recognizing that some lesions that are histologically proven to be DFSP can present without nodularity and with epidermal or dermal atrophy. This change in the nomenclature was first proposed by Lambert et al23 and was reiterated by Page and Assaad.16 Perhaps a greater awareness that DFSP can present as atrophic lesions without nodules could lead to earlier diagnosis and decreased morbidity with smaller curative surgeries when the lesions are recognized at an earlier stage. The atrophic variant of DFSP does not carry a different prognosis compared with the traditional variant; Mohs micrographic surgery is still the treatment of choice, providing a low rate of recurrence. Atrophic DFSP should be kept in the differential diagnosis for atrophic, depressed lesions, particularly those seen on the trunks of women or on the lower extremities of children. 

Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous tumor of intermediate malignancy that is known to be locally aggressive.1 It is thought to be of fibrohistiocytic origin and accounts for 1% of all soft tissue malignancies.2 DFSP occurs in men and women with equal incidence, mostly on the trunk and less commonly on the proximal extremities, with a higher incidence in Caucasians. Most patients present between the second and fifth decades, though the disease can be noted in any age group and any anatomic location.3

Four clinical variants of early DFSP are thought to exist: confluent nodular lesions forming a sclerotic plaque, keloidlike sclerotic plaque, tumor, and atrophic plaque.4,5 The usual clinical appearance of DFSP at an early stage is as a slow-growing, asymptomatic plaque or nodule. The tumor's gross pathology is of a gray-white mass involving the dermis and subcutis; histologically, it is a poorly circumscribed infiltrative spindle cell tumor. The spindle cells, which are CD34+, are arranged in a storiform pattern described as a dense, poorly circumscribed, monomorphic cell proliferation arranged in fascicles that often reach and infiltrate the hypodermis.6,7 The 3 recognized histologic variants of DFSP are fibrosarcomatous, plaquelike, and myxoid forms.8 The infiltrating pattern accounts for the tumor's common recurrence after excision and the need for wide excision or Mohs micrographic surgery for curative removal.2,3,9-11 One recent review of atrophic DFSP implicated chromosomal translocations or the formation of supernumerary ring chromosomes in the pathogenesis of DFSP.12 These chromosomal events result in the fusion of the collagen type 1α1 gene with the platelet-derived growth factor-β chain gene. How this mutation could contribute to the atrophic phenotype is unknown.12 This review documents only 25 cases of atrophic DFSP in the literature. We present a case involving a woman who had an atrophic DFSP treated successfully with Mohs micrographic surgery and review 35 cases in the literature regarding this rare presentation of DFSP. 

Case Report

A 41-year-old white woman presented with a 12-year history of a well-demarcated, scalloped, markedly depressed, reddish brown, slightly firm, 4x5-cm plaque on the right chest (Figure 1). On initial evaluation, the patient denied prior trauma to the area or any past manipulation of the lesion. The patient's preoperative clinical differential diagnosis included atrophoderma of Pasini and Pierini, anetoderma, morphea, and lipoatrophy.

A punch biopsy of the lesion was performed. Results revealed a spindle cell neoplasm that was thought to be a dermatofibroma. The entire lesion was subsequently excised. Histopathology results of the excision specimen demonstrated atrophy of the dermis and a permeative spindle cell neoplasm with scattered multinucleated giant cells involving the dermis and underlying soft tissue with a few areas of a storiform growth pattern (Figure 2). The lesion also was diffusely immunoreactive for CD34 and extended to the margins of the specimen. A diagnosis of DFSP was made, and the patient was treated with Mohs micrographic surgery. Three stages of surgery were performed, and the final defect was 7.0x8.5 cm. The patient elected to allow the wound to heal by secondary intention. There was no evidence of recurrence 12 months after the procedure.

Comment

The atrophic presentation of DFSP is the rarest variant of this infrequent neoplasm. Although this subject was recently reviewed, there are several other important issues in the literature that need to be clarified regarding this unusual phenotype.12 For a lesion to be classified as atrophic, there should be both clinical and histologic evidence of atrophy. When the epidermis is atrophic, the result is shiny smooth skin clinically and flattening of the rete ridges histopathologically. Conversely, when the dermis or subcutaneous tissue is atrophic, the result is a loss in skin thickness and a corresponding loss of collagen bundles or subcutaneous fat histopathologically.13

Epidermal atrophy is commonly noted histologically in DFSP cases that present in the usual fashion.14,15 Only rarely has DFSP presented as a clinically depressed lesion.16-20 Even more rare is a documentation of dermal atrophy.12,21 We report a case of DFSP in which the initial lesion was an atrophic depression of the skin lacking nodularity and histologically demonstrating significant dermal atrophy.

A number of cases have been reported describing atrophic presentations of DFSP (Table 1).4,5,8,12,16-26 However, as Davis and Sanchez8 noted, rarely does a so-called atrophic DFSP present as a visible depression in the skin.16-21 Clearly, there is some discrepancy in the literature as to the nature of atrophy in relation to the clinical presentation of DFSP. Some authors have even speculated that the atrophic variant of DFSP is nothing more than an early presentation of the more usual DFSP prior to the formation of nodules.4 However, the fact that our patient had her lesion for 12 years prior to treatment without the formation of a nodular component indicates that the atrophic variant of DFSP is a real entity.

Table 2 demonstrates the sex and anatomic location of the patients in the 35 reported cases of DFSP described as atrophic or morpheaform, including the present case. The majority (20/35) of cases have been in female patients, and the most common location in both sexes has been the trunk (24/35). The next most common location was the lower extremity (7/35).

Table 3 documents the age and anatomic location of the 9 cases clinically described as resembling lipoatrophy, atrophoderma or anetoderma, or that were significantly clinically depressed based on clinical photographs, ie, the cases most similar to the one we now present.4,16,19-21,25 Three of the 9 cases were on the trunks of females aged 16 to 41 years. Interestingly, 4 of the remaining 6 cases were on the lower extremities of children aged 18 months to 16 years.

A number of conclusions can be drawn from this data. First, atrophic variants of DFSP tend to occur most often on the trunk, as do the usual variants of DFSP. However, the atrophic variants tend to occur more often in females as opposed to the standard presentation of DFSP, which occurs with equal frequency in males and females. In addition, a distinction exists in the presentation of atrophic lesions, which can have either a morpheaform or a more clinically depressed appearance, mimicking such disorders as anetoderma, atrophoderma, or lipoatrophy. We report such a case mimicking atrophoderma, and we contend that this is the rarest presentation of atrophic DFSP.

One final entity in the differential diagnosis of a depressed plaque on the trunk would be an atrophic dermatofibroma. The dermatofibroma, a well-known and benign cousin of DFSP, is often noted to have some dermal atrophy grossly with lateral pressure, described as a dimple sign.27 As Requena and Reichel28 pointed out, even when there is a central depression over a dermatofibroma without lateral pressure, no true loss of the dermis is seen histopathologically. As such, this central depression doesn't represent true dermal atrophy.28 However, the dermatofibroma also can present as a depressed lesion demonstrating thinning of the dermis histologically, and this variety of dermatofibroma has been described as atrophic.28-31 Although a recently published article recommended considering a diagnosis of atrophic dermatofibroma in the case of "atrophic, depressed lesions on the upper body of middle-aged women,"31 we would maintain that atrophic DFSP also should be considered in the differential diagnosis.

One possibility to clarify the imprecision in the literature in relation to the clinical presentation of DFSP would be to eliminate protuberans from the name, thereby recognizing that some lesions that are histologically proven to be DFSP can present without nodularity and with epidermal or dermal atrophy. This change in the nomenclature was first proposed by Lambert et al23 and was reiterated by Page and Assaad.16 Perhaps a greater awareness that DFSP can present as atrophic lesions without nodules could lead to earlier diagnosis and decreased morbidity with smaller curative surgeries when the lesions are recognized at an earlier stage. The atrophic variant of DFSP does not carry a different prognosis compared with the traditional variant; Mohs micrographic surgery is still the treatment of choice, providing a low rate of recurrence. Atrophic DFSP should be kept in the differential diagnosis for atrophic, depressed lesions, particularly those seen on the trunks of women or on the lower extremities of children. 

Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous tumor of intermediate malignancy that is known to be locally aggressive.1 It is thought to be of fibrohistiocytic origin and accounts for 1% of all soft tissue malignancies.2 DFSP occurs in men and women with equal incidence, mostly on the trunk and less commonly on the proximal extremities, with a higher incidence in Caucasians. Most patients present between the second and fifth decades, though the disease can be noted in any age group and any anatomic location.3

Four clinical variants of early DFSP are thought to exist: confluent nodular lesions forming a sclerotic plaque, keloidlike sclerotic plaque, tumor, and atrophic plaque.4,5 The usual clinical appearance of DFSP at an early stage is as a slow-growing, asymptomatic plaque or nodule. The tumor's gross pathology is of a gray-white mass involving the dermis and subcutis; histologically, it is a poorly circumscribed infiltrative spindle cell tumor. The spindle cells, which are CD34+, are arranged in a storiform pattern described as a dense, poorly circumscribed, monomorphic cell proliferation arranged in fascicles that often reach and infiltrate the hypodermis.6,7 The 3 recognized histologic variants of DFSP are fibrosarcomatous, plaquelike, and myxoid forms.8 The infiltrating pattern accounts for the tumor's common recurrence after excision and the need for wide excision or Mohs micrographic surgery for curative removal.2,3,9-11 One recent review of atrophic DFSP implicated chromosomal translocations or the formation of supernumerary ring chromosomes in the pathogenesis of DFSP.12 These chromosomal events result in the fusion of the collagen type 1α1 gene with the platelet-derived growth factor-β chain gene. How this mutation could contribute to the atrophic phenotype is unknown.12 This review documents only 25 cases of atrophic DFSP in the literature. We present a case involving a woman who had an atrophic DFSP treated successfully with Mohs micrographic surgery and review 35 cases in the literature regarding this rare presentation of DFSP. 

Case Report

A 41-year-old white woman presented with a 12-year history of a well-demarcated, scalloped, markedly depressed, reddish brown, slightly firm, 4x5-cm plaque on the right chest (Figure 1). On initial evaluation, the patient denied prior trauma to the area or any past manipulation of the lesion. The patient's preoperative clinical differential diagnosis included atrophoderma of Pasini and Pierini, anetoderma, morphea, and lipoatrophy.

A punch biopsy of the lesion was performed. Results revealed a spindle cell neoplasm that was thought to be a dermatofibroma. The entire lesion was subsequently excised. Histopathology results of the excision specimen demonstrated atrophy of the dermis and a permeative spindle cell neoplasm with scattered multinucleated giant cells involving the dermis and underlying soft tissue with a few areas of a storiform growth pattern (Figure 2). The lesion also was diffusely immunoreactive for CD34 and extended to the margins of the specimen. A diagnosis of DFSP was made, and the patient was treated with Mohs micrographic surgery. Three stages of surgery were performed, and the final defect was 7.0x8.5 cm. The patient elected to allow the wound to heal by secondary intention. There was no evidence of recurrence 12 months after the procedure.

Comment

The atrophic presentation of DFSP is the rarest variant of this infrequent neoplasm. Although this subject was recently reviewed, there are several other important issues in the literature that need to be clarified regarding this unusual phenotype.12 For a lesion to be classified as atrophic, there should be both clinical and histologic evidence of atrophy. When the epidermis is atrophic, the result is shiny smooth skin clinically and flattening of the rete ridges histopathologically. Conversely, when the dermis or subcutaneous tissue is atrophic, the result is a loss in skin thickness and a corresponding loss of collagen bundles or subcutaneous fat histopathologically.13

Epidermal atrophy is commonly noted histologically in DFSP cases that present in the usual fashion.14,15 Only rarely has DFSP presented as a clinically depressed lesion.16-20 Even more rare is a documentation of dermal atrophy.12,21 We report a case of DFSP in which the initial lesion was an atrophic depression of the skin lacking nodularity and histologically demonstrating significant dermal atrophy.

A number of cases have been reported describing atrophic presentations of DFSP (Table 1).4,5,8,12,16-26 However, as Davis and Sanchez8 noted, rarely does a so-called atrophic DFSP present as a visible depression in the skin.16-21 Clearly, there is some discrepancy in the literature as to the nature of atrophy in relation to the clinical presentation of DFSP. Some authors have even speculated that the atrophic variant of DFSP is nothing more than an early presentation of the more usual DFSP prior to the formation of nodules.4 However, the fact that our patient had her lesion for 12 years prior to treatment without the formation of a nodular component indicates that the atrophic variant of DFSP is a real entity.

Table 2 demonstrates the sex and anatomic location of the patients in the 35 reported cases of DFSP described as atrophic or morpheaform, including the present case. The majority (20/35) of cases have been in female patients, and the most common location in both sexes has been the trunk (24/35). The next most common location was the lower extremity (7/35).

Table 3 documents the age and anatomic location of the 9 cases clinically described as resembling lipoatrophy, atrophoderma or anetoderma, or that were significantly clinically depressed based on clinical photographs, ie, the cases most similar to the one we now present.4,16,19-21,25 Three of the 9 cases were on the trunks of females aged 16 to 41 years. Interestingly, 4 of the remaining 6 cases were on the lower extremities of children aged 18 months to 16 years.

A number of conclusions can be drawn from this data. First, atrophic variants of DFSP tend to occur most often on the trunk, as do the usual variants of DFSP. However, the atrophic variants tend to occur more often in females as opposed to the standard presentation of DFSP, which occurs with equal frequency in males and females. In addition, a distinction exists in the presentation of atrophic lesions, which can have either a morpheaform or a more clinically depressed appearance, mimicking such disorders as anetoderma, atrophoderma, or lipoatrophy. We report such a case mimicking atrophoderma, and we contend that this is the rarest presentation of atrophic DFSP.

One final entity in the differential diagnosis of a depressed plaque on the trunk would be an atrophic dermatofibroma. The dermatofibroma, a well-known and benign cousin of DFSP, is often noted to have some dermal atrophy grossly with lateral pressure, described as a dimple sign.27 As Requena and Reichel28 pointed out, even when there is a central depression over a dermatofibroma without lateral pressure, no true loss of the dermis is seen histopathologically. As such, this central depression doesn't represent true dermal atrophy.28 However, the dermatofibroma also can present as a depressed lesion demonstrating thinning of the dermis histologically, and this variety of dermatofibroma has been described as atrophic.28-31 Although a recently published article recommended considering a diagnosis of atrophic dermatofibroma in the case of "atrophic, depressed lesions on the upper body of middle-aged women,"31 we would maintain that atrophic DFSP also should be considered in the differential diagnosis.

One possibility to clarify the imprecision in the literature in relation to the clinical presentation of DFSP would be to eliminate protuberans from the name, thereby recognizing that some lesions that are histologically proven to be DFSP can present without nodularity and with epidermal or dermal atrophy. This change in the nomenclature was first proposed by Lambert et al23 and was reiterated by Page and Assaad.16 Perhaps a greater awareness that DFSP can present as atrophic lesions without nodules could lead to earlier diagnosis and decreased morbidity with smaller curative surgeries when the lesions are recognized at an earlier stage. The atrophic variant of DFSP does not carry a different prognosis compared with the traditional variant; Mohs micrographic surgery is still the treatment of choice, providing a low rate of recurrence. Atrophic DFSP should be kept in the differential diagnosis for atrophic, depressed lesions, particularly those seen on the trunks of women or on the lower extremities of children. 

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.