Cutis

A keratoacanthoma centrifugum marginatum (KACM) may pose a diagnostic and therapeutic challenge. Clinically and histologically, it may resemble mycobacterial or deep fungal infection or halogenoderma. Therapy can be challenging because the lesion can expand to a great size. We report on a patient with multiple lesions of KACM. The diagnostic difficulty and the therapeutic failure of imiquimod, intralesional methotrexate (MTX), and isotretinoin, as well as the therapeutic success of 5-fluorouracil (5-FU) cream, are discussed.

Although Belisario first referred to the large annular keratoacanthoma (KA) as keratoacanthoma centrifugum marginatum (KACM) in 1965, a variety of names have been applied to this entity, including squamous cell pseudoepithelioma, aggregated KA, coral-reef KA, nodulo-vegetating KA, KA centrifugum, and multinodular KA.1,2 KACM is characterized by central regression with concomitant growth and expansion of the periphery but no tendencies toward complete regression in contrast to other types of KAs. A proper diagnosis can be challenging because clinically and histologically the lesions may resemble halogenoderma or infections such as verrucous tuberculosis or deep fungal infection. Therapy can be challenging because the lesions can reach a great size. The present case illustrates this diagnostic and therapeutic conundrum in a patient with multiple KACM. 

Case Report

A 78-year-old man being treated for more than 9 years for multiple KAs on his upper and lower extremities presented with an annular plaque with an elevated crusted keratotic border on the right ankle. Over the course of a year, the plaque enlarged to measure 20 cm (Figure 1). Additional annular and arciform plaques ranging from 13 to 16 cm developed on both legs over this period. The patient's medical history included type 2 diabetes mellitus, peripheral vascular disease, hyperlipidemia, coronary artery disease, and benign prostatic hypertrophy. There was no history of internal malignancy or family history of KAs. Chromoblastomycosis, verrucous tuberculosis, and KACM were considered in the differential diagnosis. No fungi or mycobacteria were isolated in any of the several skin biopsies or cultures performed. There were frequent secondary bacterial infections of the lesions, which were treated with appropriate antibiotics.

A wedge biopsy of the large annular plaque was performed. The area of regression showed fibrosis with an overlying flattened epidermis. The peripheral expanding area showed aggregations of large epithelial cells with abundant pink cytoplasm emanating from the epidermis (Figure 2), while the trailing clearing areas showed fibrosis. Some of the aggregations had jagged outlines that were lined by atypical epithelial cells (Figure 3). Within the aggregations, there were varying degrees of keratinization with presence of parakeratotic cornified cells and neutrophils centrally (Figure 3). Although the histopathologic changes were compatible for KACM, the differential diagnosis included halogenoderma and infectious etiology such as deep fungal or mycobacterial infection. The clinical and histopathologic findings, the lack of halogen exposure, the history of multiple KAs, and the absence of organisms in tissue biopsy and culture results led to the diagnosis of multiple KACM.

Once the frequent secondary bacterial infections were under control, the patient was treated with several therapeutic agents including imiquimod cream, intralesional methotrexate (MTX), and 5-fluorouracil (5-FU) cream. Because the lesions were multiple and large, surgery was not performed. As chemoprophylaxis, isotretinoin was initiated at 40 mg/d and then increased to 60 mg/d after 4 months. The total duration of isotretinoin therapy was 13 months. Along with the usual mucocutaneous side effects, the patient experienced back pain and mild mood alteration after the dose was increased. His complete blood count, liver function tests, and serum triglyceride levels all remained within reference range throughout the duration of therapy.

At the time of initiation of isotretinoin, MTX was injected into 2 different areas of the peripheral border of the largest lesion 3 weeks apart. The doses totaled 68 mg and 60 mg at each site, respectively. In addition, imiquimod under occlusion was applied every night to several of the lesions for the next 7 months. None of the lesions treated with either intralesional MTX or imiquimod resolved. Subsequent to the failure of imiquimod and MTX, 5-FU cream was applied to all of the annular lesions while the patient was still receiving isotretinoin therapy. Clinical response to 5-FU was apparent after 2 months. A complete clinical resolution, however, occurred over a period of 11 months (Figure 4). Isotretinoin was discontinued 5 months prior to the completion of the course of 5-FU cream.

While receiving isotretinoin therapy, the patient developed several more solitary KAs, and the annular lesions enlarged to varying sizes. The solitary KAs were managed either surgically or with liquid nitrogen, depending on the size. The new annular lesions were promptly eradicated with 5-FU cream. 

Comment

Some of the largest lesions of KACM (measuring ≥20 cm) have been reported to occur on the lower extremities.3-6 The lesions enlarged over a period of 10 months to several years with no tendency to regress completely, similar to our patient. All of these reported large lesions of the legs were successfully treated surgically. The diagnostic difficulty was not addressed in these previously reported cases; in our case, however, the initial lack of the characteristic exophytic rolled and shiny peripheral border and the frequent secondary bacterial infections contributed to the difficulty in accurate diagnosis. Initially, an infectious etiology such as chromoblastomycosis and verrucous tuberculosis was suspected. Histopathologically, the distinguishing exoendophytic architecture present at the periphery of KACM was not present; instead, the pathologic changes were confined to the superficial dermis, which consisted of jagged outlined epithelial aggregations that were difficult to distinguish from pseuodoepitheliomatous hyperplasia secondary to deep fungal or mycobacterial infection or halogenoderma. The history, clinicopathologic correlation, and negative culture results eventually led to the diagnosis of KACM.

A variety of treatment modalities have been employed successfully for KAs, including surgical excision, intralesional MTX, intralesional and topical 5-FU, intralesional bleomycin, and isotretinoin.2 Isotretinoin has been advocated as both a prophylactic and therapeutic agent for skin cancers, especially in the setting of multiple lesions.7-9 A relatively high dose (1–3 mg/kg) is required, even for prophylactic outcome. A low dose, in the range of 5 to 10 mg/d, is neither prophylactic nor therapeutic.10,11 The side effects, which include elevated triglyceride levels, mucocutaneous reactions, and hyperostotic axial skeletal changes, limit the use of isotretinoin. The efficacy of retinoids in the prophylaxis and treatment of KA and KACM also has been reported by several authors.12-15 The dosage of isotretinoin ranged from 1 to 3 mg/kg per day with a response observed as early as within one week to several months. In our case, despite adequate duration and relative high doses of isotretinoin, there was no prophylactic or therapeutic effect as evidenced by the patient's continual development of nodular KAs without any of the existing KAs regressing while he was receiving isotretinoin therapy. The patient experienced the usual mucocutaneous side effects. His backache and the changes in his mood were suspected to be the side effects of isotretinoin, as well.

Intralesional MTX for the treatment of KAs has been reported to be effective with a regimen of 1 to 3 injections not exceeding a total dose of 100 mg, resulting in resolution of the KAs in 2 to 4 weeks.16-18 In our patient, although the 2 sites were injected with adequate amounts of MTX, the treatment was unsuccessful. In retrospect, intralesional therapy was unreasonable because of the large amounts of MTX that would have been required. The 2 treated sites accounted for less than 10% of the surface area of the lesions.

The rationale for imiquimod therapy in our patient was 2-fold. First, imiquimod is an immune response modifier emerging as an effective therapy for superficial carcinomas of the skin.19-22 Most therapies available for superficial skin carcinomas also have been applied to KAs. Second, because human papillomavirus has been found to be present in KA, though not consistently,23-26 we were hopeful that imiquimod would have a therapeutic effect for KACM similar to that for condyloma. Despite daily application of the cream for 7 months to some of the lesions, far beyond the 6 to 12 weeks' duration recommended for basal cell carcinomas,19,27 imiquimod had no effect.

Both topical and intralesional 5-FU, a thymine analog, have been reported to be effective therapies for solitary and multiple KAs, though there is no reported case of KACM treated with either topical or intralesional 5-FU. A dramatic resolution has been observed as early as one week after treatment using topical 5-FU, but the usual duration of therapy was 3 to 4 weeks.28-30 In contrast to these reports, encouraging signs of resolution were present in our patient after 2 months of therapy, and complete resolution occurred over a period of many months, not weeks. Despite the apparent efficacy of 5-FU, we cannot exclude the possibility that the regression of the lesions was the natural course of the neoplasm, especially when KAs are known to regress without any therapeutic intervention. The evidence supporting topical 5-FU being efficacious is that there was prompt resolution when the cream was applied to the new lesions.

The nature of KA and KACM, whether or not the neoplasm is a squamous cell carcinoma (SCC), has been controversial. A few authors assert that a KA is an SCC.5,31,32 We consider KA and its variants, including KACM, as one type of SCC encountered in the skin. A few well-documented cases of metastases of KAs to the lymph nodes have been reported.31,33 At the molecular level, KA has been shown to overexpress p53,34 a tumor suppressor gene that has been associated with a variety of malignant neoplasms. In contrast to other types of SCC, a complete regression, believed to be an immune-mediated process by some,35,36 is a unique characteristic of KA. The exact mechanism by which a KA regresses, however, remains largely a mystery. LeBoit37 has hinted that solving this mystery may have far-reaching applications. We agree.

A keratoacanthoma centrifugum marginatum (KACM) may pose a diagnostic and therapeutic challenge. Clinically and histologically, it may resemble mycobacterial or deep fungal infection or halogenoderma. Therapy can be challenging because the lesion can expand to a great size. We report on a patient with multiple lesions of KACM. The diagnostic difficulty and the therapeutic failure of imiquimod, intralesional methotrexate (MTX), and isotretinoin, as well as the therapeutic success of 5-fluorouracil (5-FU) cream, are discussed.

Although Belisario first referred to the large annular keratoacanthoma (KA) as keratoacanthoma centrifugum marginatum (KACM) in 1965, a variety of names have been applied to this entity, including squamous cell pseudoepithelioma, aggregated KA, coral-reef KA, nodulo-vegetating KA, KA centrifugum, and multinodular KA.1,2 KACM is characterized by central regression with concomitant growth and expansion of the periphery but no tendencies toward complete regression in contrast to other types of KAs. A proper diagnosis can be challenging because clinically and histologically the lesions may resemble halogenoderma or infections such as verrucous tuberculosis or deep fungal infection. Therapy can be challenging because the lesions can reach a great size. The present case illustrates this diagnostic and therapeutic conundrum in a patient with multiple KACM. 

Case Report

A 78-year-old man being treated for more than 9 years for multiple KAs on his upper and lower extremities presented with an annular plaque with an elevated crusted keratotic border on the right ankle. Over the course of a year, the plaque enlarged to measure 20 cm (Figure 1). Additional annular and arciform plaques ranging from 13 to 16 cm developed on both legs over this period. The patient's medical history included type 2 diabetes mellitus, peripheral vascular disease, hyperlipidemia, coronary artery disease, and benign prostatic hypertrophy. There was no history of internal malignancy or family history of KAs. Chromoblastomycosis, verrucous tuberculosis, and KACM were considered in the differential diagnosis. No fungi or mycobacteria were isolated in any of the several skin biopsies or cultures performed. There were frequent secondary bacterial infections of the lesions, which were treated with appropriate antibiotics.

A wedge biopsy of the large annular plaque was performed. The area of regression showed fibrosis with an overlying flattened epidermis. The peripheral expanding area showed aggregations of large epithelial cells with abundant pink cytoplasm emanating from the epidermis (Figure 2), while the trailing clearing areas showed fibrosis. Some of the aggregations had jagged outlines that were lined by atypical epithelial cells (Figure 3). Within the aggregations, there were varying degrees of keratinization with presence of parakeratotic cornified cells and neutrophils centrally (Figure 3). Although the histopathologic changes were compatible for KACM, the differential diagnosis included halogenoderma and infectious etiology such as deep fungal or mycobacterial infection. The clinical and histopathologic findings, the lack of halogen exposure, the history of multiple KAs, and the absence of organisms in tissue biopsy and culture results led to the diagnosis of multiple KACM.

Once the frequent secondary bacterial infections were under control, the patient was treated with several therapeutic agents including imiquimod cream, intralesional methotrexate (MTX), and 5-fluorouracil (5-FU) cream. Because the lesions were multiple and large, surgery was not performed. As chemoprophylaxis, isotretinoin was initiated at 40 mg/d and then increased to 60 mg/d after 4 months. The total duration of isotretinoin therapy was 13 months. Along with the usual mucocutaneous side effects, the patient experienced back pain and mild mood alteration after the dose was increased. His complete blood count, liver function tests, and serum triglyceride levels all remained within reference range throughout the duration of therapy.

At the time of initiation of isotretinoin, MTX was injected into 2 different areas of the peripheral border of the largest lesion 3 weeks apart. The doses totaled 68 mg and 60 mg at each site, respectively. In addition, imiquimod under occlusion was applied every night to several of the lesions for the next 7 months. None of the lesions treated with either intralesional MTX or imiquimod resolved. Subsequent to the failure of imiquimod and MTX, 5-FU cream was applied to all of the annular lesions while the patient was still receiving isotretinoin therapy. Clinical response to 5-FU was apparent after 2 months. A complete clinical resolution, however, occurred over a period of 11 months (Figure 4). Isotretinoin was discontinued 5 months prior to the completion of the course of 5-FU cream.

While receiving isotretinoin therapy, the patient developed several more solitary KAs, and the annular lesions enlarged to varying sizes. The solitary KAs were managed either surgically or with liquid nitrogen, depending on the size. The new annular lesions were promptly eradicated with 5-FU cream. 

Comment

Some of the largest lesions of KACM (measuring ≥20 cm) have been reported to occur on the lower extremities.3-6 The lesions enlarged over a period of 10 months to several years with no tendency to regress completely, similar to our patient. All of these reported large lesions of the legs were successfully treated surgically. The diagnostic difficulty was not addressed in these previously reported cases; in our case, however, the initial lack of the characteristic exophytic rolled and shiny peripheral border and the frequent secondary bacterial infections contributed to the difficulty in accurate diagnosis. Initially, an infectious etiology such as chromoblastomycosis and verrucous tuberculosis was suspected. Histopathologically, the distinguishing exoendophytic architecture present at the periphery of KACM was not present; instead, the pathologic changes were confined to the superficial dermis, which consisted of jagged outlined epithelial aggregations that were difficult to distinguish from pseuodoepitheliomatous hyperplasia secondary to deep fungal or mycobacterial infection or halogenoderma. The history, clinicopathologic correlation, and negative culture results eventually led to the diagnosis of KACM.

A variety of treatment modalities have been employed successfully for KAs, including surgical excision, intralesional MTX, intralesional and topical 5-FU, intralesional bleomycin, and isotretinoin.2 Isotretinoin has been advocated as both a prophylactic and therapeutic agent for skin cancers, especially in the setting of multiple lesions.7-9 A relatively high dose (1–3 mg/kg) is required, even for prophylactic outcome. A low dose, in the range of 5 to 10 mg/d, is neither prophylactic nor therapeutic.10,11 The side effects, which include elevated triglyceride levels, mucocutaneous reactions, and hyperostotic axial skeletal changes, limit the use of isotretinoin. The efficacy of retinoids in the prophylaxis and treatment of KA and KACM also has been reported by several authors.12-15 The dosage of isotretinoin ranged from 1 to 3 mg/kg per day with a response observed as early as within one week to several months. In our case, despite adequate duration and relative high doses of isotretinoin, there was no prophylactic or therapeutic effect as evidenced by the patient's continual development of nodular KAs without any of the existing KAs regressing while he was receiving isotretinoin therapy. The patient experienced the usual mucocutaneous side effects. His backache and the changes in his mood were suspected to be the side effects of isotretinoin, as well.

Intralesional MTX for the treatment of KAs has been reported to be effective with a regimen of 1 to 3 injections not exceeding a total dose of 100 mg, resulting in resolution of the KAs in 2 to 4 weeks.16-18 In our patient, although the 2 sites were injected with adequate amounts of MTX, the treatment was unsuccessful. In retrospect, intralesional therapy was unreasonable because of the large amounts of MTX that would have been required. The 2 treated sites accounted for less than 10% of the surface area of the lesions.

The rationale for imiquimod therapy in our patient was 2-fold. First, imiquimod is an immune response modifier emerging as an effective therapy for superficial carcinomas of the skin.19-22 Most therapies available for superficial skin carcinomas also have been applied to KAs. Second, because human papillomavirus has been found to be present in KA, though not consistently,23-26 we were hopeful that imiquimod would have a therapeutic effect for KACM similar to that for condyloma. Despite daily application of the cream for 7 months to some of the lesions, far beyond the 6 to 12 weeks' duration recommended for basal cell carcinomas,19,27 imiquimod had no effect.

Both topical and intralesional 5-FU, a thymine analog, have been reported to be effective therapies for solitary and multiple KAs, though there is no reported case of KACM treated with either topical or intralesional 5-FU. A dramatic resolution has been observed as early as one week after treatment using topical 5-FU, but the usual duration of therapy was 3 to 4 weeks.28-30 In contrast to these reports, encouraging signs of resolution were present in our patient after 2 months of therapy, and complete resolution occurred over a period of many months, not weeks. Despite the apparent efficacy of 5-FU, we cannot exclude the possibility that the regression of the lesions was the natural course of the neoplasm, especially when KAs are known to regress without any therapeutic intervention. The evidence supporting topical 5-FU being efficacious is that there was prompt resolution when the cream was applied to the new lesions.

The nature of KA and KACM, whether or not the neoplasm is a squamous cell carcinoma (SCC), has been controversial. A few authors assert that a KA is an SCC.5,31,32 We consider KA and its variants, including KACM, as one type of SCC encountered in the skin. A few well-documented cases of metastases of KAs to the lymph nodes have been reported.31,33 At the molecular level, KA has been shown to overexpress p53,34 a tumor suppressor gene that has been associated with a variety of malignant neoplasms. In contrast to other types of SCC, a complete regression, believed to be an immune-mediated process by some,35,36 is a unique characteristic of KA. The exact mechanism by which a KA regresses, however, remains largely a mystery. LeBoit37 has hinted that solving this mystery may have far-reaching applications. We agree.

A keratoacanthoma centrifugum marginatum (KACM) may pose a diagnostic and therapeutic challenge. Clinically and histologically, it may resemble mycobacterial or deep fungal infection or halogenoderma. Therapy can be challenging because the lesion can expand to a great size. We report on a patient with multiple lesions of KACM. The diagnostic difficulty and the therapeutic failure of imiquimod, intralesional methotrexate (MTX), and isotretinoin, as well as the therapeutic success of 5-fluorouracil (5-FU) cream, are discussed.

Although Belisario first referred to the large annular keratoacanthoma (KA) as keratoacanthoma centrifugum marginatum (KACM) in 1965, a variety of names have been applied to this entity, including squamous cell pseudoepithelioma, aggregated KA, coral-reef KA, nodulo-vegetating KA, KA centrifugum, and multinodular KA.1,2 KACM is characterized by central regression with concomitant growth and expansion of the periphery but no tendencies toward complete regression in contrast to other types of KAs. A proper diagnosis can be challenging because clinically and histologically the lesions may resemble halogenoderma or infections such as verrucous tuberculosis or deep fungal infection. Therapy can be challenging because the lesions can reach a great size. The present case illustrates this diagnostic and therapeutic conundrum in a patient with multiple KACM. 

Case Report

A 78-year-old man being treated for more than 9 years for multiple KAs on his upper and lower extremities presented with an annular plaque with an elevated crusted keratotic border on the right ankle. Over the course of a year, the plaque enlarged to measure 20 cm (Figure 1). Additional annular and arciform plaques ranging from 13 to 16 cm developed on both legs over this period. The patient's medical history included type 2 diabetes mellitus, peripheral vascular disease, hyperlipidemia, coronary artery disease, and benign prostatic hypertrophy. There was no history of internal malignancy or family history of KAs. Chromoblastomycosis, verrucous tuberculosis, and KACM were considered in the differential diagnosis. No fungi or mycobacteria were isolated in any of the several skin biopsies or cultures performed. There were frequent secondary bacterial infections of the lesions, which were treated with appropriate antibiotics.

A wedge biopsy of the large annular plaque was performed. The area of regression showed fibrosis with an overlying flattened epidermis. The peripheral expanding area showed aggregations of large epithelial cells with abundant pink cytoplasm emanating from the epidermis (Figure 2), while the trailing clearing areas showed fibrosis. Some of the aggregations had jagged outlines that were lined by atypical epithelial cells (Figure 3). Within the aggregations, there were varying degrees of keratinization with presence of parakeratotic cornified cells and neutrophils centrally (Figure 3). Although the histopathologic changes were compatible for KACM, the differential diagnosis included halogenoderma and infectious etiology such as deep fungal or mycobacterial infection. The clinical and histopathologic findings, the lack of halogen exposure, the history of multiple KAs, and the absence of organisms in tissue biopsy and culture results led to the diagnosis of multiple KACM.

Once the frequent secondary bacterial infections were under control, the patient was treated with several therapeutic agents including imiquimod cream, intralesional methotrexate (MTX), and 5-fluorouracil (5-FU) cream. Because the lesions were multiple and large, surgery was not performed. As chemoprophylaxis, isotretinoin was initiated at 40 mg/d and then increased to 60 mg/d after 4 months. The total duration of isotretinoin therapy was 13 months. Along with the usual mucocutaneous side effects, the patient experienced back pain and mild mood alteration after the dose was increased. His complete blood count, liver function tests, and serum triglyceride levels all remained within reference range throughout the duration of therapy.

At the time of initiation of isotretinoin, MTX was injected into 2 different areas of the peripheral border of the largest lesion 3 weeks apart. The doses totaled 68 mg and 60 mg at each site, respectively. In addition, imiquimod under occlusion was applied every night to several of the lesions for the next 7 months. None of the lesions treated with either intralesional MTX or imiquimod resolved. Subsequent to the failure of imiquimod and MTX, 5-FU cream was applied to all of the annular lesions while the patient was still receiving isotretinoin therapy. Clinical response to 5-FU was apparent after 2 months. A complete clinical resolution, however, occurred over a period of 11 months (Figure 4). Isotretinoin was discontinued 5 months prior to the completion of the course of 5-FU cream.

While receiving isotretinoin therapy, the patient developed several more solitary KAs, and the annular lesions enlarged to varying sizes. The solitary KAs were managed either surgically or with liquid nitrogen, depending on the size. The new annular lesions were promptly eradicated with 5-FU cream. 

Comment

Some of the largest lesions of KACM (measuring ≥20 cm) have been reported to occur on the lower extremities.3-6 The lesions enlarged over a period of 10 months to several years with no tendency to regress completely, similar to our patient. All of these reported large lesions of the legs were successfully treated surgically. The diagnostic difficulty was not addressed in these previously reported cases; in our case, however, the initial lack of the characteristic exophytic rolled and shiny peripheral border and the frequent secondary bacterial infections contributed to the difficulty in accurate diagnosis. Initially, an infectious etiology such as chromoblastomycosis and verrucous tuberculosis was suspected. Histopathologically, the distinguishing exoendophytic architecture present at the periphery of KACM was not present; instead, the pathologic changes were confined to the superficial dermis, which consisted of jagged outlined epithelial aggregations that were difficult to distinguish from pseuodoepitheliomatous hyperplasia secondary to deep fungal or mycobacterial infection or halogenoderma. The history, clinicopathologic correlation, and negative culture results eventually led to the diagnosis of KACM.

A variety of treatment modalities have been employed successfully for KAs, including surgical excision, intralesional MTX, intralesional and topical 5-FU, intralesional bleomycin, and isotretinoin.2 Isotretinoin has been advocated as both a prophylactic and therapeutic agent for skin cancers, especially in the setting of multiple lesions.7-9 A relatively high dose (1–3 mg/kg) is required, even for prophylactic outcome. A low dose, in the range of 5 to 10 mg/d, is neither prophylactic nor therapeutic.10,11 The side effects, which include elevated triglyceride levels, mucocutaneous reactions, and hyperostotic axial skeletal changes, limit the use of isotretinoin. The efficacy of retinoids in the prophylaxis and treatment of KA and KACM also has been reported by several authors.12-15 The dosage of isotretinoin ranged from 1 to 3 mg/kg per day with a response observed as early as within one week to several months. In our case, despite adequate duration and relative high doses of isotretinoin, there was no prophylactic or therapeutic effect as evidenced by the patient's continual development of nodular KAs without any of the existing KAs regressing while he was receiving isotretinoin therapy. The patient experienced the usual mucocutaneous side effects. His backache and the changes in his mood were suspected to be the side effects of isotretinoin, as well.

Intralesional MTX for the treatment of KAs has been reported to be effective with a regimen of 1 to 3 injections not exceeding a total dose of 100 mg, resulting in resolution of the KAs in 2 to 4 weeks.16-18 In our patient, although the 2 sites were injected with adequate amounts of MTX, the treatment was unsuccessful. In retrospect, intralesional therapy was unreasonable because of the large amounts of MTX that would have been required. The 2 treated sites accounted for less than 10% of the surface area of the lesions.

The rationale for imiquimod therapy in our patient was 2-fold. First, imiquimod is an immune response modifier emerging as an effective therapy for superficial carcinomas of the skin.19-22 Most therapies available for superficial skin carcinomas also have been applied to KAs. Second, because human papillomavirus has been found to be present in KA, though not consistently,23-26 we were hopeful that imiquimod would have a therapeutic effect for KACM similar to that for condyloma. Despite daily application of the cream for 7 months to some of the lesions, far beyond the 6 to 12 weeks' duration recommended for basal cell carcinomas,19,27 imiquimod had no effect.

Both topical and intralesional 5-FU, a thymine analog, have been reported to be effective therapies for solitary and multiple KAs, though there is no reported case of KACM treated with either topical or intralesional 5-FU. A dramatic resolution has been observed as early as one week after treatment using topical 5-FU, but the usual duration of therapy was 3 to 4 weeks.28-30 In contrast to these reports, encouraging signs of resolution were present in our patient after 2 months of therapy, and complete resolution occurred over a period of many months, not weeks. Despite the apparent efficacy of 5-FU, we cannot exclude the possibility that the regression of the lesions was the natural course of the neoplasm, especially when KAs are known to regress without any therapeutic intervention. The evidence supporting topical 5-FU being efficacious is that there was prompt resolution when the cream was applied to the new lesions.

The nature of KA and KACM, whether or not the neoplasm is a squamous cell carcinoma (SCC), has been controversial. A few authors assert that a KA is an SCC.5,31,32 We consider KA and its variants, including KACM, as one type of SCC encountered in the skin. A few well-documented cases of metastases of KAs to the lymph nodes have been reported.31,33 At the molecular level, KA has been shown to overexpress p53,34 a tumor suppressor gene that has been associated with a variety of malignant neoplasms. In contrast to other types of SCC, a complete regression, believed to be an immune-mediated process by some,35,36 is a unique characteristic of KA. The exact mechanism by which a KA regresses, however, remains largely a mystery. LeBoit37 has hinted that solving this mystery may have far-reaching applications. We agree.

Acanthamoebae are free-living protozoa that are present ubiquitously in the environment. They are found in water, soil, and air samples throughout the world and have been cultured from the throats of both healthy and immunocompromised asymptomatic individuals.1,2 The life cycle of Acanthamoeba consists of a feeding and replicating trophozoite stage and a resilient, dormant cystic stage.1 At least 16 species of Acanthamoeba have been identified, of which several have been associated with human disease.1,2

The pathogenic potential of Acanthamoeba was established in animal models by Culbertson et al in 1959.3 The earliest report of human infection by Acanthamoeba may have been reported by Kernohan et al4 in 1960 when they attributed a brain granuloma to an Iodamoeba butschlii infection. The organism was later identified as Acanthamoeba. Since then, more than 100 cases of granulomatous amebic encephalitis (GAE) and hundreds of cases of amebic keratitis have been reported.2 GAE is a slowly progressive, fatal central nervous system (CNS) infection primarily affecting immunocompromised patients.1-9 Amebic keratitis is a sight-threatening infection that affects the general population of developing countries, as well as healthy individuals worldwide who wear contact lenses.1 Cutaneous acanthamebiasis, often a manifestation of disseminated extracerebral disease, is extremely rare, with only 37 cases, including the present report, described to date.5-33 Dissemination of the ameba is postulated to occur by hematogenous spread from a primary focus within the skin or the upper or lower respiratory tract.14 The prognosis of cutaneous acanthamebiasis is dismal, with a mortality rate of at least 74% in patients without CNS involvement and 100% in patients with CNS involvement.

We present a patient with acquired immunodeficiency syndrome (AIDS) and disseminated cutaneous acanthamebiasis with possible involvement of the CNS whose general condition and cutaneous lesions improved with a prompt antiparasitic therapeutic regimen that included sulfadiazine and antiretroviral therapy. 

Case Report

A 51-year-old woman with AIDS, a history of cytomegalovirus retinitis, and multiple episodes of Pneumocystis carinii pneumonia was admitted to the hospital with numerous pruritic, painful cutaneous nodules that had developed over a 2-week period. The initial skin lesion appeared as a small papule on her right forearm that slowly enlarged as other nodules appeared in a generalized distribution over the next 5 to 7 days. Some of the nodules ulcerated, draining purulent fluid and forming necrotic eschars. On admission, the patient reported no chills or fever but complained of photophobia and a 1-week history of severe headache localized to the right frontal region.

On physical examination, the patient was cachectic, photophobic, oriented yet drowsy, and in mild respiratory distress. Multiple intradermal and subcutaneous nodules (0.5–2 cm in diameter), some with overlying erythema, were present on her face, arms, chest, back, legs, and thighs. A deep ulcer covered by a 3x4-cm eschar was noted on the dorsum of her right forearm and an additional ulcer was noted on her leg (Figure 1). Ophthalmologic examination revealed no evidence of active disease and neurologic examination was nonfocal.

The patient's most recent CD4 count and viral load were 3 cells/mm-3 and 34,875 copies/mL-1, respectively. A deep incision biopsy of a skin nodule on the patient's right thigh was performed. Bacterial tissue cultures of the thigh nodule grew Enterococcus faecalis. Mycobacterial, fungal, and viral culture results of the tissue were negative. Blood culture results were negative for bacterial, mycobacterial, and fungal growth. Serum cryptococcus and histoplasma antigens were negative, as was the urine histoplasma antigen.

Histologic sections of the skin biopsy showed an intense inflammatory infiltrate of lymphocytes within the deep dermis, subcutis, and fascia, admixed with neutrophils, plasma cells, and eosinophils. Diffuse areas of collagen and fat necrosis were noted throughout the areas of inflammation. Numerous Acanthamoeba trophozoites measuring 10 to 15 µm were scattered throughout the inflammatory infiltrate. These structures, best visualized on hematoxylin-eosin (H&E) staining, contained a centrally located nucleus and clear nucleolus surrounded by copious vacuolated cytoplasm. Fewer encysted forms were present, and they contained a scalloped inner endocystic wall surrounded by a less ruffled outer ectocyst wall (Figure 2). Culture of the tissue sample was performed in a medium inoculated with Escherichia coli as a nutrient source; results of the culture demonstrated trophozoite forms with acanthopodia formation, confirming the organism to be Acanthamoeba.

Computed tomography (CT) of the brain was unremarkable; however, magnetic resonance imaging of the brain showed cerebral volume loss and nonspecific foci of increased signal intensity in the periventricular and subcortical white matter, basal ganglia, and posterior fossa with no abnormal enhancement. These findings were interpreted to be secondary to human immunodeficiency virus (HIV) infection. Cerebrospinal fluid (CSF) analysis showed one mononuclear leukocyte and 2 erythrocytes. The CSF glucose and protein levels were 50 mg/dL and 17 mg/dL, respectively (reference ranges, 50–75 mg/dL and 15–45 mg/dL, respectively). CSF culture results were sterile and were negative for cryptococcus antigen. Results of microscopic examination showed no evidence of amebic organisms in the CSF.

Three days after admission, the patient was prescribed a therapeutic regimen of pentamidine 160 mg intravenously once a day and oral 5-flucytosine 1 g every 6 hours. Unfortunately, new nodules continued to appear, and some of the existing nodules enlarged and ulcerated forming necrotic eschars. Because of the patient's poor response, sulfadiazine and highly active antiretroviral therapy (HAART) were added to the therapeutic regimen. The appearance of new nodules subsequently ceased, and the patient experienced slow regression of existing nodules. The patient's general well being also improved as her photophobia resolved and her severe headaches, which initially required intravenous narcotic analgesia, diminished.

After completing a 14-day course of intravenous pentamidine, the patient was discharged in stable condition on a therapeutic regimen of 5-flucytosine 1 g every 6 hours, sulfadiazine 1 g every 6 hours, and HAART therapy consisting of tenofovir 300 mg/d, lamivudine 300 mg/d, and abacavir 600 mg/d. Three months after discharge, no evidence of CNS decline was noted. Improvement in the patient's general condition and in her cutaneous lesions continues despite less than optimal compliance with the treatment regimen.

Comment

Cutaneous lesions are present in 90% of patients with disseminated acanthamebiasis, making it the most common sign of disseminated disease. The primary cutaneous lesions in patients with acanthamebiasis are polymorphic and are commonly described as intradermal6 or subcutaneous6,18,26 nodules that are erythematous6,10,11,16 or violaceous,10,22 ranging from a few millimeters to several centimeters in diameter. In addition, papules,7,8,16 pustules,14 plaques,12 cellulitis,28 and intramuscular abscesses23 all have been described. Lesions can be pruritic,14 tender,6,11 or nontender,10,18 and they typically evolve through a course of enlargement, suppuration, and ulceration. A necrotic eschar may develop and then slough, thereby deepening the ulcer.16 The differential diagnosis of nodular and ulcerative cutaneous lesions is broad and includes deep fungal or mycobacterial infections, pyoderma gangrenosum, and vasculitis.

The histologic findings of the cutaneous lesions in acanthamebiasis may show granulomatous inflammation, which is notably absent in immunocompromised patients with severe disease and CNS involvement.19,27 Other reported histopathologic features include leukocytoclastic5,7 or necrotizing10,11 vasculitis, panniculitis,14,22,27 and acute and/or chronic inflammation.9,16,20,21,23,30 The diagnosis of Acanthamoeba infection requires visualization of amebic trophozoites and/or cysts, which may be found perivascularly. Ideally, a culture should be performed on the organisms with subsequent morphologic examination. Trophozoites and cysts both contain a single nucleus and a nucleolus. Acanthamoeba cysts vary in size depending on the species, but commonly range from 13 to 30 mm in diameter. Trophozoites contain slender projections termed acanthopodia, which aid in motitility.34 A finding of Acanthamoeba requires a high index of suspicion because the ameba have been mistaken for macrophages, Rhinosporidium seeberi, Cryptococcus neoformans, Prototheca wickerhamii, and Blastomyces dermatitides.11,24 An incorrect diagnosis of a deep fungal infection is sometimes made when histologic evaluation is done with Gomori methenamine silver or periodic acid–Schiff stains. The amebic cyst wall picks up those stains in a pattern reminiscent of a fungal cell wall, leading to the missed diagnosis.24

Among the 37 reported cases of cutaneous acanthamebiasis, 27 patients were HIV positive (aged 8 months–60 years; mean, 34 years).5-23 A history of AIDS-defining illnesses was reported in 74% of patients, and CD4 counts ranged from 0 to 566 cells/mm-3 (median, 28 cells/mm-3). In addition to cutaneous involvement, patients with HIV/AIDS also presented with concomitant amebic sinusitis (13/27), osteomyelitis (3/27), uveitis (2/27), pneumonitis (2/27), and infection of the CNS (confirmed in 2/27; suspected but unconfirmed in 4/27). Involvement of the nasal septum (5/27) and palate (4/27) was not uncommon. Symptoms on presentation often included fever,5,7,11,20 nasal congestion/discharge,8,9,13,21 epistaxis,13,14 and cough.14 Patients with presumed or confirmed CNS involvement developed headaches,17,21 fever,20 altered mental status,17,20 hemiparesis,19 lethargy,17 spasticity,21 and seizures.14

The mortality rate for cutaneous acanthamebiasis in the setting of HIV/AIDS without evidence of CNS involvement is at least 75%. Of the patients who died, the duration of illness until death ranged from 9 weeks to 2 years (average, 7.5 months). The development of CNS symptoms in HIV-positive patients with cutaneous acanthamebiasis resulted in death in all patients within days to weeks of the appearance of symptoms.17,19,25,27,30

In addition to patients with HIV/AIDS, cutaneous acanthamebiasis has been described in 7 non-HIV, immunosuppressed patients aged 7 to 61 years (mean, 35 years). Six of the patients were transplant recipients,24-29 and one patient was receiving long-term steroid therapy.30 Five patients died from their infections, and 2 patients were treated successfully (resolution of all lesions). In one successfully treated case, immunosuppression was lowered, and the patient was given pentamidine with 5-flourocytosine.29 In another successfully treated case, immunosuppression was maintained, and the patient responded to pentamidine and topical chlorhexidine and ketoconazole cream.26

In exogenously immunocompromised patients with cutaneous acanthamebiasis, additional sites of involvement included CNS (3/7), lungs (2/7), adrenal glands (2/7), kidney (1/7), pancreas (1/7), and bone (1/7). In the 3 patients with CNS involvement, cutaneous lesions preceded neurological symptoms in 2 patients,27,30 and the lesions occurred after the expression of focal neurological symptoms in one patient.25 This suggests that cutaneous lesions can be either an initial or late manifestation of disseminated acanthamebiasis.

Although cutaneous acanthamebiasis is largely a disease of immunocompromised patients, 3 patients with this disease (aged 5 years, 24 years, and unknown) were apparently healthy.31-33 In one patient, the history of illness could not be elicited33; in the other 2 patients, lesions developed at a site of prior trauma.32,33 In these otherwise healthy patients, the course of the illness was more protracted than in the immunocompromised patients. Lesions remained localized from 6 months to more than a year prior to involvement of other sites. In 2 cases, the symptoms were exacerbated after the patients received systemic steroids.32,33 All 3 patients died after infection spread to the CNS.31-33

In any patient with disseminated cutaneous acanthamebiasis presenting with neurological symptoms, a diagnosis of GAE, meningitis, or meningoencephalitis is often made postmortem.19,20,27,30 Premortem diagnosis may be facilitated by a brain biopsy because radiographic or CSF analyses are often nonspecific or nondiagnostic. There are case reports of patients with disseminated disease and CNS involvement whose CSF never yielded amebic organisms. However, there also are reports of 3 patients with strictly localized CNS involvement who had amebic organisms on CSF wet mounts.35,36 In patients with disseminated acanthamebiasis and extensive CNS involvement documented at autopsy, premortem CSF findings were within reference range20 or showed intermediate elevation in white blood cell count and protein.19,27,30 Radiographic findings in patients with GAE may show hypodense lesions on CT scans, which may enhance on T2-weighted magnetic resonance imaging.37,38 Isodense or hyperdense lesions also are seen on brain CT scans of patients with GAE; however, CT findings are normal in up to 12% of patients with GAE.38 Normal magnetic resonance imaging findings in patients with CNS involvement also have been reported.36 In the present case, no definitive evidence of CNS infection was noted on CSF or radiographic analysis.

The treatment for acanthamebiasis has not been well established and is based largely on in vitro sensitivity of the organism to a number of chemotherapeutic agents, and on a small number of reports of successfully treated cases. The Table lists common antimicrobial agents used in the treatment of patients with disseminated cutaneous acanthamebiasis and their reported response. The Table includes only immunocompromised patients with disseminated cutaneous acanthamebiasis without evidence of CNS involvement. Patients with CNS involvement were excluded because the rapid course of illness in those patients makes evaluation of therapy difficult.

Although few patients experienced marked resolution of disseminated cutaneous acanthamebiasis, it appears that the inclusion of 5-flucytosine in the therapeutic regimen was associated with the greatest number of improved cases. In general, a multidrug regimen appears to be more effective than monotherapy. Surgical debridement of affected areas has been beneficial in some cases,13,22 and it should be considered in patients with localized disease, in particular. Topical chlorhexidine has been used adjunctively in some successfully treated cases of cutaneous acanthamebiasis.22,29 In exogenously immunocompromised patients, lowering the dose of the immunosuppressants led to disease-free survival in one patient but had no benefit in 2 other patients,24,27 presumably because of the advanced stage of the disease.

In the present case, our patient's disease initially progressed despite the administration of pentamidine and 5-flucytosine. Stabilization and subsequent resolution of the lesions began after the addition of sulfadiazine and HAART to the therapeutic regimen. In patients with HIV disease and acanthamebiasis, there are no reports demonstrating whether the administration of antiretrovirals can alter the course of the disease. Although sulfonamides have not been used frequently in the treatment of disseminated acanthamebiasis, the utility of sulfonamides in the treatment of Acanthamoeba infection has been shown by Allen and Culbertson,39 who reported that experimental animal infection with Acanthamoeba species can be both prevented and cured with sulfadiazine. Additionally, Cleland et al40 reported improvement in a patient with Acanthamoeba meningoencephalitis who was treated with sulfamethazine, though long-term follow-up was not feasible. Furthermore, Singhal et al35 reported the successful treatment of 2 immunocompetent patients with Acanthamoeba CNS infection using a combination of trimethoprim/ sulfamethoxazole, ketoconazole, and rifampin. These data, combined with the observations of our patient's therapeutic course, suggest that sulfadiazine therapy was important to our patient's clinical improvement and thus should be strongly considered in the treatment of disseminated Acanthamoeba infection. Sulfonamides, however, must be used with caution in patients with HIV/AIDS because of this patient population's high incidence of adverse reactions, especially fever, myalgia, and rash.41

Amebic infections, though rare, have become increasingly recognized in recent years as a result of the emergence of AIDS and the availability of effective immunosuppressive regimens for the prevention of transplant rejection and the treatment of autoimmune diseases. Prompt diagnosis of acanthamebiasis is crucial to a patient's survival because delay in treatment has led to rapid deterioration and death in all reported cases. Although optimal therapy has not been established for this condition, previously reported cases and this case report suggest that efforts to restore the patient's immune system, as well as treatment with a multidrug regimen containing 5-flucytosine and sulfadiazine, may offer the best chance of long-term survival.

Acknowledgment—We would like to thank Cynthia Sears, MD, for her active role in the management of the patient and review of the manuscript. 

Acanthamoebae are free-living protozoa that are present ubiquitously in the environment. They are found in water, soil, and air samples throughout the world and have been cultured from the throats of both healthy and immunocompromised asymptomatic individuals.1,2 The life cycle of Acanthamoeba consists of a feeding and replicating trophozoite stage and a resilient, dormant cystic stage.1 At least 16 species of Acanthamoeba have been identified, of which several have been associated with human disease.1,2

The pathogenic potential of Acanthamoeba was established in animal models by Culbertson et al in 1959.3 The earliest report of human infection by Acanthamoeba may have been reported by Kernohan et al4 in 1960 when they attributed a brain granuloma to an Iodamoeba butschlii infection. The organism was later identified as Acanthamoeba. Since then, more than 100 cases of granulomatous amebic encephalitis (GAE) and hundreds of cases of amebic keratitis have been reported.2 GAE is a slowly progressive, fatal central nervous system (CNS) infection primarily affecting immunocompromised patients.1-9 Amebic keratitis is a sight-threatening infection that affects the general population of developing countries, as well as healthy individuals worldwide who wear contact lenses.1 Cutaneous acanthamebiasis, often a manifestation of disseminated extracerebral disease, is extremely rare, with only 37 cases, including the present report, described to date.5-33 Dissemination of the ameba is postulated to occur by hematogenous spread from a primary focus within the skin or the upper or lower respiratory tract.14 The prognosis of cutaneous acanthamebiasis is dismal, with a mortality rate of at least 74% in patients without CNS involvement and 100% in patients with CNS involvement.

We present a patient with acquired immunodeficiency syndrome (AIDS) and disseminated cutaneous acanthamebiasis with possible involvement of the CNS whose general condition and cutaneous lesions improved with a prompt antiparasitic therapeutic regimen that included sulfadiazine and antiretroviral therapy. 

Case Report

A 51-year-old woman with AIDS, a history of cytomegalovirus retinitis, and multiple episodes of Pneumocystis carinii pneumonia was admitted to the hospital with numerous pruritic, painful cutaneous nodules that had developed over a 2-week period. The initial skin lesion appeared as a small papule on her right forearm that slowly enlarged as other nodules appeared in a generalized distribution over the next 5 to 7 days. Some of the nodules ulcerated, draining purulent fluid and forming necrotic eschars. On admission, the patient reported no chills or fever but complained of photophobia and a 1-week history of severe headache localized to the right frontal region.

On physical examination, the patient was cachectic, photophobic, oriented yet drowsy, and in mild respiratory distress. Multiple intradermal and subcutaneous nodules (0.5–2 cm in diameter), some with overlying erythema, were present on her face, arms, chest, back, legs, and thighs. A deep ulcer covered by a 3x4-cm eschar was noted on the dorsum of her right forearm and an additional ulcer was noted on her leg (Figure 1). Ophthalmologic examination revealed no evidence of active disease and neurologic examination was nonfocal.

The patient's most recent CD4 count and viral load were 3 cells/mm-3 and 34,875 copies/mL-1, respectively. A deep incision biopsy of a skin nodule on the patient's right thigh was performed. Bacterial tissue cultures of the thigh nodule grew Enterococcus faecalis. Mycobacterial, fungal, and viral culture results of the tissue were negative. Blood culture results were negative for bacterial, mycobacterial, and fungal growth. Serum cryptococcus and histoplasma antigens were negative, as was the urine histoplasma antigen.

Histologic sections of the skin biopsy showed an intense inflammatory infiltrate of lymphocytes within the deep dermis, subcutis, and fascia, admixed with neutrophils, plasma cells, and eosinophils. Diffuse areas of collagen and fat necrosis were noted throughout the areas of inflammation. Numerous Acanthamoeba trophozoites measuring 10 to 15 µm were scattered throughout the inflammatory infiltrate. These structures, best visualized on hematoxylin-eosin (H&E) staining, contained a centrally located nucleus and clear nucleolus surrounded by copious vacuolated cytoplasm. Fewer encysted forms were present, and they contained a scalloped inner endocystic wall surrounded by a less ruffled outer ectocyst wall (Figure 2). Culture of the tissue sample was performed in a medium inoculated with Escherichia coli as a nutrient source; results of the culture demonstrated trophozoite forms with acanthopodia formation, confirming the organism to be Acanthamoeba.

Computed tomography (CT) of the brain was unremarkable; however, magnetic resonance imaging of the brain showed cerebral volume loss and nonspecific foci of increased signal intensity in the periventricular and subcortical white matter, basal ganglia, and posterior fossa with no abnormal enhancement. These findings were interpreted to be secondary to human immunodeficiency virus (HIV) infection. Cerebrospinal fluid (CSF) analysis showed one mononuclear leukocyte and 2 erythrocytes. The CSF glucose and protein levels were 50 mg/dL and 17 mg/dL, respectively (reference ranges, 50–75 mg/dL and 15–45 mg/dL, respectively). CSF culture results were sterile and were negative for cryptococcus antigen. Results of microscopic examination showed no evidence of amebic organisms in the CSF.

Three days after admission, the patient was prescribed a therapeutic regimen of pentamidine 160 mg intravenously once a day and oral 5-flucytosine 1 g every 6 hours. Unfortunately, new nodules continued to appear, and some of the existing nodules enlarged and ulcerated forming necrotic eschars. Because of the patient's poor response, sulfadiazine and highly active antiretroviral therapy (HAART) were added to the therapeutic regimen. The appearance of new nodules subsequently ceased, and the patient experienced slow regression of existing nodules. The patient's general well being also improved as her photophobia resolved and her severe headaches, which initially required intravenous narcotic analgesia, diminished.

After completing a 14-day course of intravenous pentamidine, the patient was discharged in stable condition on a therapeutic regimen of 5-flucytosine 1 g every 6 hours, sulfadiazine 1 g every 6 hours, and HAART therapy consisting of tenofovir 300 mg/d, lamivudine 300 mg/d, and abacavir 600 mg/d. Three months after discharge, no evidence of CNS decline was noted. Improvement in the patient's general condition and in her cutaneous lesions continues despite less than optimal compliance with the treatment regimen.

Comment

Cutaneous lesions are present in 90% of patients with disseminated acanthamebiasis, making it the most common sign of disseminated disease. The primary cutaneous lesions in patients with acanthamebiasis are polymorphic and are commonly described as intradermal6 or subcutaneous6,18,26 nodules that are erythematous6,10,11,16 or violaceous,10,22 ranging from a few millimeters to several centimeters in diameter. In addition, papules,7,8,16 pustules,14 plaques,12 cellulitis,28 and intramuscular abscesses23 all have been described. Lesions can be pruritic,14 tender,6,11 or nontender,10,18 and they typically evolve through a course of enlargement, suppuration, and ulceration. A necrotic eschar may develop and then slough, thereby deepening the ulcer.16 The differential diagnosis of nodular and ulcerative cutaneous lesions is broad and includes deep fungal or mycobacterial infections, pyoderma gangrenosum, and vasculitis.

The histologic findings of the cutaneous lesions in acanthamebiasis may show granulomatous inflammation, which is notably absent in immunocompromised patients with severe disease and CNS involvement.19,27 Other reported histopathologic features include leukocytoclastic5,7 or necrotizing10,11 vasculitis, panniculitis,14,22,27 and acute and/or chronic inflammation.9,16,20,21,23,30 The diagnosis of Acanthamoeba infection requires visualization of amebic trophozoites and/or cysts, which may be found perivascularly. Ideally, a culture should be performed on the organisms with subsequent morphologic examination. Trophozoites and cysts both contain a single nucleus and a nucleolus. Acanthamoeba cysts vary in size depending on the species, but commonly range from 13 to 30 mm in diameter. Trophozoites contain slender projections termed acanthopodia, which aid in motitility.34 A finding of Acanthamoeba requires a high index of suspicion because the ameba have been mistaken for macrophages, Rhinosporidium seeberi, Cryptococcus neoformans, Prototheca wickerhamii, and Blastomyces dermatitides.11,24 An incorrect diagnosis of a deep fungal infection is sometimes made when histologic evaluation is done with Gomori methenamine silver or periodic acid–Schiff stains. The amebic cyst wall picks up those stains in a pattern reminiscent of a fungal cell wall, leading to the missed diagnosis.24

Among the 37 reported cases of cutaneous acanthamebiasis, 27 patients were HIV positive (aged 8 months–60 years; mean, 34 years).5-23 A history of AIDS-defining illnesses was reported in 74% of patients, and CD4 counts ranged from 0 to 566 cells/mm-3 (median, 28 cells/mm-3). In addition to cutaneous involvement, patients with HIV/AIDS also presented with concomitant amebic sinusitis (13/27), osteomyelitis (3/27), uveitis (2/27), pneumonitis (2/27), and infection of the CNS (confirmed in 2/27; suspected but unconfirmed in 4/27). Involvement of the nasal septum (5/27) and palate (4/27) was not uncommon. Symptoms on presentation often included fever,5,7,11,20 nasal congestion/discharge,8,9,13,21 epistaxis,13,14 and cough.14 Patients with presumed or confirmed CNS involvement developed headaches,17,21 fever,20 altered mental status,17,20 hemiparesis,19 lethargy,17 spasticity,21 and seizures.14

The mortality rate for cutaneous acanthamebiasis in the setting of HIV/AIDS without evidence of CNS involvement is at least 75%. Of the patients who died, the duration of illness until death ranged from 9 weeks to 2 years (average, 7.5 months). The development of CNS symptoms in HIV-positive patients with cutaneous acanthamebiasis resulted in death in all patients within days to weeks of the appearance of symptoms.17,19,25,27,30

In addition to patients with HIV/AIDS, cutaneous acanthamebiasis has been described in 7 non-HIV, immunosuppressed patients aged 7 to 61 years (mean, 35 years). Six of the patients were transplant recipients,24-29 and one patient was receiving long-term steroid therapy.30 Five patients died from their infections, and 2 patients were treated successfully (resolution of all lesions). In one successfully treated case, immunosuppression was lowered, and the patient was given pentamidine with 5-flourocytosine.29 In another successfully treated case, immunosuppression was maintained, and the patient responded to pentamidine and topical chlorhexidine and ketoconazole cream.26

In exogenously immunocompromised patients with cutaneous acanthamebiasis, additional sites of involvement included CNS (3/7), lungs (2/7), adrenal glands (2/7), kidney (1/7), pancreas (1/7), and bone (1/7). In the 3 patients with CNS involvement, cutaneous lesions preceded neurological symptoms in 2 patients,27,30 and the lesions occurred after the expression of focal neurological symptoms in one patient.25 This suggests that cutaneous lesions can be either an initial or late manifestation of disseminated acanthamebiasis.

Although cutaneous acanthamebiasis is largely a disease of immunocompromised patients, 3 patients with this disease (aged 5 years, 24 years, and unknown) were apparently healthy.31-33 In one patient, the history of illness could not be elicited33; in the other 2 patients, lesions developed at a site of prior trauma.32,33 In these otherwise healthy patients, the course of the illness was more protracted than in the immunocompromised patients. Lesions remained localized from 6 months to more than a year prior to involvement of other sites. In 2 cases, the symptoms were exacerbated after the patients received systemic steroids.32,33 All 3 patients died after infection spread to the CNS.31-33

In any patient with disseminated cutaneous acanthamebiasis presenting with neurological symptoms, a diagnosis of GAE, meningitis, or meningoencephalitis is often made postmortem.19,20,27,30 Premortem diagnosis may be facilitated by a brain biopsy because radiographic or CSF analyses are often nonspecific or nondiagnostic. There are case reports of patients with disseminated disease and CNS involvement whose CSF never yielded amebic organisms. However, there also are reports of 3 patients with strictly localized CNS involvement who had amebic organisms on CSF wet mounts.35,36 In patients with disseminated acanthamebiasis and extensive CNS involvement documented at autopsy, premortem CSF findings were within reference range20 or showed intermediate elevation in white blood cell count and protein.19,27,30 Radiographic findings in patients with GAE may show hypodense lesions on CT scans, which may enhance on T2-weighted magnetic resonance imaging.37,38 Isodense or hyperdense lesions also are seen on brain CT scans of patients with GAE; however, CT findings are normal in up to 12% of patients with GAE.38 Normal magnetic resonance imaging findings in patients with CNS involvement also have been reported.36 In the present case, no definitive evidence of CNS infection was noted on CSF or radiographic analysis.

The treatment for acanthamebiasis has not been well established and is based largely on in vitro sensitivity of the organism to a number of chemotherapeutic agents, and on a small number of reports of successfully treated cases. The Table lists common antimicrobial agents used in the treatment of patients with disseminated cutaneous acanthamebiasis and their reported response. The Table includes only immunocompromised patients with disseminated cutaneous acanthamebiasis without evidence of CNS involvement. Patients with CNS involvement were excluded because the rapid course of illness in those patients makes evaluation of therapy difficult.

Although few patients experienced marked resolution of disseminated cutaneous acanthamebiasis, it appears that the inclusion of 5-flucytosine in the therapeutic regimen was associated with the greatest number of improved cases. In general, a multidrug regimen appears to be more effective than monotherapy. Surgical debridement of affected areas has been beneficial in some cases,13,22 and it should be considered in patients with localized disease, in particular. Topical chlorhexidine has been used adjunctively in some successfully treated cases of cutaneous acanthamebiasis.22,29 In exogenously immunocompromised patients, lowering the dose of the immunosuppressants led to disease-free survival in one patient but had no benefit in 2 other patients,24,27 presumably because of the advanced stage of the disease.

In the present case, our patient's disease initially progressed despite the administration of pentamidine and 5-flucytosine. Stabilization and subsequent resolution of the lesions began after the addition of sulfadiazine and HAART to the therapeutic regimen. In patients with HIV disease and acanthamebiasis, there are no reports demonstrating whether the administration of antiretrovirals can alter the course of the disease. Although sulfonamides have not been used frequently in the treatment of disseminated acanthamebiasis, the utility of sulfonamides in the treatment of Acanthamoeba infection has been shown by Allen and Culbertson,39 who reported that experimental animal infection with Acanthamoeba species can be both prevented and cured with sulfadiazine. Additionally, Cleland et al40 reported improvement in a patient with Acanthamoeba meningoencephalitis who was treated with sulfamethazine, though long-term follow-up was not feasible. Furthermore, Singhal et al35 reported the successful treatment of 2 immunocompetent patients with Acanthamoeba CNS infection using a combination of trimethoprim/ sulfamethoxazole, ketoconazole, and rifampin. These data, combined with the observations of our patient's therapeutic course, suggest that sulfadiazine therapy was important to our patient's clinical improvement and thus should be strongly considered in the treatment of disseminated Acanthamoeba infection. Sulfonamides, however, must be used with caution in patients with HIV/AIDS because of this patient population's high incidence of adverse reactions, especially fever, myalgia, and rash.41

Amebic infections, though rare, have become increasingly recognized in recent years as a result of the emergence of AIDS and the availability of effective immunosuppressive regimens for the prevention of transplant rejection and the treatment of autoimmune diseases. Prompt diagnosis of acanthamebiasis is crucial to a patient's survival because delay in treatment has led to rapid deterioration and death in all reported cases. Although optimal therapy has not been established for this condition, previously reported cases and this case report suggest that efforts to restore the patient's immune system, as well as treatment with a multidrug regimen containing 5-flucytosine and sulfadiazine, may offer the best chance of long-term survival.

Acknowledgment—We would like to thank Cynthia Sears, MD, for her active role in the management of the patient and review of the manuscript. 

Acanthamoebae are free-living protozoa that are present ubiquitously in the environment. They are found in water, soil, and air samples throughout the world and have been cultured from the throats of both healthy and immunocompromised asymptomatic individuals.1,2 The life cycle of Acanthamoeba consists of a feeding and replicating trophozoite stage and a resilient, dormant cystic stage.1 At least 16 species of Acanthamoeba have been identified, of which several have been associated with human disease.1,2

The pathogenic potential of Acanthamoeba was established in animal models by Culbertson et al in 1959.3 The earliest report of human infection by Acanthamoeba may have been reported by Kernohan et al4 in 1960 when they attributed a brain granuloma to an Iodamoeba butschlii infection. The organism was later identified as Acanthamoeba. Since then, more than 100 cases of granulomatous amebic encephalitis (GAE) and hundreds of cases of amebic keratitis have been reported.2 GAE is a slowly progressive, fatal central nervous system (CNS) infection primarily affecting immunocompromised patients.1-9 Amebic keratitis is a sight-threatening infection that affects the general population of developing countries, as well as healthy individuals worldwide who wear contact lenses.1 Cutaneous acanthamebiasis, often a manifestation of disseminated extracerebral disease, is extremely rare, with only 37 cases, including the present report, described to date.5-33 Dissemination of the ameba is postulated to occur by hematogenous spread from a primary focus within the skin or the upper or lower respiratory tract.14 The prognosis of cutaneous acanthamebiasis is dismal, with a mortality rate of at least 74% in patients without CNS involvement and 100% in patients with CNS involvement.

We present a patient with acquired immunodeficiency syndrome (AIDS) and disseminated cutaneous acanthamebiasis with possible involvement of the CNS whose general condition and cutaneous lesions improved with a prompt antiparasitic therapeutic regimen that included sulfadiazine and antiretroviral therapy. 

Case Report

A 51-year-old woman with AIDS, a history of cytomegalovirus retinitis, and multiple episodes of Pneumocystis carinii pneumonia was admitted to the hospital with numerous pruritic, painful cutaneous nodules that had developed over a 2-week period. The initial skin lesion appeared as a small papule on her right forearm that slowly enlarged as other nodules appeared in a generalized distribution over the next 5 to 7 days. Some of the nodules ulcerated, draining purulent fluid and forming necrotic eschars. On admission, the patient reported no chills or fever but complained of photophobia and a 1-week history of severe headache localized to the right frontal region.

On physical examination, the patient was cachectic, photophobic, oriented yet drowsy, and in mild respiratory distress. Multiple intradermal and subcutaneous nodules (0.5–2 cm in diameter), some with overlying erythema, were present on her face, arms, chest, back, legs, and thighs. A deep ulcer covered by a 3x4-cm eschar was noted on the dorsum of her right forearm and an additional ulcer was noted on her leg (Figure 1). Ophthalmologic examination revealed no evidence of active disease and neurologic examination was nonfocal.

The patient's most recent CD4 count and viral load were 3 cells/mm-3 and 34,875 copies/mL-1, respectively. A deep incision biopsy of a skin nodule on the patient's right thigh was performed. Bacterial tissue cultures of the thigh nodule grew Enterococcus faecalis. Mycobacterial, fungal, and viral culture results of the tissue were negative. Blood culture results were negative for bacterial, mycobacterial, and fungal growth. Serum cryptococcus and histoplasma antigens were negative, as was the urine histoplasma antigen.

Histologic sections of the skin biopsy showed an intense inflammatory infiltrate of lymphocytes within the deep dermis, subcutis, and fascia, admixed with neutrophils, plasma cells, and eosinophils. Diffuse areas of collagen and fat necrosis were noted throughout the areas of inflammation. Numerous Acanthamoeba trophozoites measuring 10 to 15 µm were scattered throughout the inflammatory infiltrate. These structures, best visualized on hematoxylin-eosin (H&E) staining, contained a centrally located nucleus and clear nucleolus surrounded by copious vacuolated cytoplasm. Fewer encysted forms were present, and they contained a scalloped inner endocystic wall surrounded by a less ruffled outer ectocyst wall (Figure 2). Culture of the tissue sample was performed in a medium inoculated with Escherichia coli as a nutrient source; results of the culture demonstrated trophozoite forms with acanthopodia formation, confirming the organism to be Acanthamoeba.

Computed tomography (CT) of the brain was unremarkable; however, magnetic resonance imaging of the brain showed cerebral volume loss and nonspecific foci of increased signal intensity in the periventricular and subcortical white matter, basal ganglia, and posterior fossa with no abnormal enhancement. These findings were interpreted to be secondary to human immunodeficiency virus (HIV) infection. Cerebrospinal fluid (CSF) analysis showed one mononuclear leukocyte and 2 erythrocytes. The CSF glucose and protein levels were 50 mg/dL and 17 mg/dL, respectively (reference ranges, 50–75 mg/dL and 15–45 mg/dL, respectively). CSF culture results were sterile and were negative for cryptococcus antigen. Results of microscopic examination showed no evidence of amebic organisms in the CSF.

Three days after admission, the patient was prescribed a therapeutic regimen of pentamidine 160 mg intravenously once a day and oral 5-flucytosine 1 g every 6 hours. Unfortunately, new nodules continued to appear, and some of the existing nodules enlarged and ulcerated forming necrotic eschars. Because of the patient's poor response, sulfadiazine and highly active antiretroviral therapy (HAART) were added to the therapeutic regimen. The appearance of new nodules subsequently ceased, and the patient experienced slow regression of existing nodules. The patient's general well being also improved as her photophobia resolved and her severe headaches, which initially required intravenous narcotic analgesia, diminished.

After completing a 14-day course of intravenous pentamidine, the patient was discharged in stable condition on a therapeutic regimen of 5-flucytosine 1 g every 6 hours, sulfadiazine 1 g every 6 hours, and HAART therapy consisting of tenofovir 300 mg/d, lamivudine 300 mg/d, and abacavir 600 mg/d. Three months after discharge, no evidence of CNS decline was noted. Improvement in the patient's general condition and in her cutaneous lesions continues despite less than optimal compliance with the treatment regimen.

Comment

Cutaneous lesions are present in 90% of patients with disseminated acanthamebiasis, making it the most common sign of disseminated disease. The primary cutaneous lesions in patients with acanthamebiasis are polymorphic and are commonly described as intradermal6 or subcutaneous6,18,26 nodules that are erythematous6,10,11,16 or violaceous,10,22 ranging from a few millimeters to several centimeters in diameter. In addition, papules,7,8,16 pustules,14 plaques,12 cellulitis,28 and intramuscular abscesses23 all have been described. Lesions can be pruritic,14 tender,6,11 or nontender,10,18 and they typically evolve through a course of enlargement, suppuration, and ulceration. A necrotic eschar may develop and then slough, thereby deepening the ulcer.16 The differential diagnosis of nodular and ulcerative cutaneous lesions is broad and includes deep fungal or mycobacterial infections, pyoderma gangrenosum, and vasculitis.

The histologic findings of the cutaneous lesions in acanthamebiasis may show granulomatous inflammation, which is notably absent in immunocompromised patients with severe disease and CNS involvement.19,27 Other reported histopathologic features include leukocytoclastic5,7 or necrotizing10,11 vasculitis, panniculitis,14,22,27 and acute and/or chronic inflammation.9,16,20,21,23,30 The diagnosis of Acanthamoeba infection requires visualization of amebic trophozoites and/or cysts, which may be found perivascularly. Ideally, a culture should be performed on the organisms with subsequent morphologic examination. Trophozoites and cysts both contain a single nucleus and a nucleolus. Acanthamoeba cysts vary in size depending on the species, but commonly range from 13 to 30 mm in diameter. Trophozoites contain slender projections termed acanthopodia, which aid in motitility.34 A finding of Acanthamoeba requires a high index of suspicion because the ameba have been mistaken for macrophages, Rhinosporidium seeberi, Cryptococcus neoformans, Prototheca wickerhamii, and Blastomyces dermatitides.11,24 An incorrect diagnosis of a deep fungal infection is sometimes made when histologic evaluation is done with Gomori methenamine silver or periodic acid–Schiff stains. The amebic cyst wall picks up those stains in a pattern reminiscent of a fungal cell wall, leading to the missed diagnosis.24

Among the 37 reported cases of cutaneous acanthamebiasis, 27 patients were HIV positive (aged 8 months–60 years; mean, 34 years).5-23 A history of AIDS-defining illnesses was reported in 74% of patients, and CD4 counts ranged from 0 to 566 cells/mm-3 (median, 28 cells/mm-3). In addition to cutaneous involvement, patients with HIV/AIDS also presented with concomitant amebic sinusitis (13/27), osteomyelitis (3/27), uveitis (2/27), pneumonitis (2/27), and infection of the CNS (confirmed in 2/27; suspected but unconfirmed in 4/27). Involvement of the nasal septum (5/27) and palate (4/27) was not uncommon. Symptoms on presentation often included fever,5,7,11,20 nasal congestion/discharge,8,9,13,21 epistaxis,13,14 and cough.14 Patients with presumed or confirmed CNS involvement developed headaches,17,21 fever,20 altered mental status,17,20 hemiparesis,19 lethargy,17 spasticity,21 and seizures.14

The mortality rate for cutaneous acanthamebiasis in the setting of HIV/AIDS without evidence of CNS involvement is at least 75%. Of the patients who died, the duration of illness until death ranged from 9 weeks to 2 years (average, 7.5 months). The development of CNS symptoms in HIV-positive patients with cutaneous acanthamebiasis resulted in death in all patients within days to weeks of the appearance of symptoms.17,19,25,27,30

In addition to patients with HIV/AIDS, cutaneous acanthamebiasis has been described in 7 non-HIV, immunosuppressed patients aged 7 to 61 years (mean, 35 years). Six of the patients were transplant recipients,24-29 and one patient was receiving long-term steroid therapy.30 Five patients died from their infections, and 2 patients were treated successfully (resolution of all lesions). In one successfully treated case, immunosuppression was lowered, and the patient was given pentamidine with 5-flourocytosine.29 In another successfully treated case, immunosuppression was maintained, and the patient responded to pentamidine and topical chlorhexidine and ketoconazole cream.26

In exogenously immunocompromised patients with cutaneous acanthamebiasis, additional sites of involvement included CNS (3/7), lungs (2/7), adrenal glands (2/7), kidney (1/7), pancreas (1/7), and bone (1/7). In the 3 patients with CNS involvement, cutaneous lesions preceded neurological symptoms in 2 patients,27,30 and the lesions occurred after the expression of focal neurological symptoms in one patient.25 This suggests that cutaneous lesions can be either an initial or late manifestation of disseminated acanthamebiasis.

Although cutaneous acanthamebiasis is largely a disease of immunocompromised patients, 3 patients with this disease (aged 5 years, 24 years, and unknown) were apparently healthy.31-33 In one patient, the history of illness could not be elicited33; in the other 2 patients, lesions developed at a site of prior trauma.32,33 In these otherwise healthy patients, the course of the illness was more protracted than in the immunocompromised patients. Lesions remained localized from 6 months to more than a year prior to involvement of other sites. In 2 cases, the symptoms were exacerbated after the patients received systemic steroids.32,33 All 3 patients died after infection spread to the CNS.31-33

In any patient with disseminated cutaneous acanthamebiasis presenting with neurological symptoms, a diagnosis of GAE, meningitis, or meningoencephalitis is often made postmortem.19,20,27,30 Premortem diagnosis may be facilitated by a brain biopsy because radiographic or CSF analyses are often nonspecific or nondiagnostic. There are case reports of patients with disseminated disease and CNS involvement whose CSF never yielded amebic organisms. However, there also are reports of 3 patients with strictly localized CNS involvement who had amebic organisms on CSF wet mounts.35,36 In patients with disseminated acanthamebiasis and extensive CNS involvement documented at autopsy, premortem CSF findings were within reference range20 or showed intermediate elevation in white blood cell count and protein.19,27,30 Radiographic findings in patients with GAE may show hypodense lesions on CT scans, which may enhance on T2-weighted magnetic resonance imaging.37,38 Isodense or hyperdense lesions also are seen on brain CT scans of patients with GAE; however, CT findings are normal in up to 12% of patients with GAE.38 Normal magnetic resonance imaging findings in patients with CNS involvement also have been reported.36 In the present case, no definitive evidence of CNS infection was noted on CSF or radiographic analysis.

The treatment for acanthamebiasis has not been well established and is based largely on in vitro sensitivity of the organism to a number of chemotherapeutic agents, and on a small number of reports of successfully treated cases. The Table lists common antimicrobial agents used in the treatment of patients with disseminated cutaneous acanthamebiasis and their reported response. The Table includes only immunocompromised patients with disseminated cutaneous acanthamebiasis without evidence of CNS involvement. Patients with CNS involvement were excluded because the rapid course of illness in those patients makes evaluation of therapy difficult.

Although few patients experienced marked resolution of disseminated cutaneous acanthamebiasis, it appears that the inclusion of 5-flucytosine in the therapeutic regimen was associated with the greatest number of improved cases. In general, a multidrug regimen appears to be more effective than monotherapy. Surgical debridement of affected areas has been beneficial in some cases,13,22 and it should be considered in patients with localized disease, in particular. Topical chlorhexidine has been used adjunctively in some successfully treated cases of cutaneous acanthamebiasis.22,29 In exogenously immunocompromised patients, lowering the dose of the immunosuppressants led to disease-free survival in one patient but had no benefit in 2 other patients,24,27 presumably because of the advanced stage of the disease.

In the present case, our patient's disease initially progressed despite the administration of pentamidine and 5-flucytosine. Stabilization and subsequent resolution of the lesions began after the addition of sulfadiazine and HAART to the therapeutic regimen. In patients with HIV disease and acanthamebiasis, there are no reports demonstrating whether the administration of antiretrovirals can alter the course of the disease. Although sulfonamides have not been used frequently in the treatment of disseminated acanthamebiasis, the utility of sulfonamides in the treatment of Acanthamoeba infection has been shown by Allen and Culbertson,39 who reported that experimental animal infection with Acanthamoeba species can be both prevented and cured with sulfadiazine. Additionally, Cleland et al40 reported improvement in a patient with Acanthamoeba meningoencephalitis who was treated with sulfamethazine, though long-term follow-up was not feasible. Furthermore, Singhal et al35 reported the successful treatment of 2 immunocompetent patients with Acanthamoeba CNS infection using a combination of trimethoprim/ sulfamethoxazole, ketoconazole, and rifampin. These data, combined with the observations of our patient's therapeutic course, suggest that sulfadiazine therapy was important to our patient's clinical improvement and thus should be strongly considered in the treatment of disseminated Acanthamoeba infection. Sulfonamides, however, must be used with caution in patients with HIV/AIDS because of this patient population's high incidence of adverse reactions, especially fever, myalgia, and rash.41

Amebic infections, though rare, have become increasingly recognized in recent years as a result of the emergence of AIDS and the availability of effective immunosuppressive regimens for the prevention of transplant rejection and the treatment of autoimmune diseases. Prompt diagnosis of acanthamebiasis is crucial to a patient's survival because delay in treatment has led to rapid deterioration and death in all reported cases. Although optimal therapy has not been established for this condition, previously reported cases and this case report suggest that efforts to restore the patient's immune system, as well as treatment with a multidrug regimen containing 5-flucytosine and sulfadiazine, may offer the best chance of long-term survival.

Acknowledgment—We would like to thank Cynthia Sears, MD, for her active role in the management of the patient and review of the manuscript.