Nonmelanoma Skin Cancer

Microcystic adnexal carcinoma (MAC) is a relatively uncommon adnexal neoplasm that can demonstrate locally aggressive behavior; rare instances of metastatic lesions have been reported. We report a case of a 34-year-old black man with multiple primary MACs.

Case Report
An otherwise healthy 34-year-old black man presented for evaluation of a progressive lesion on the left thigh that had been diagnosed as lichen simplex chronicus 15 years earlier. The patient stated that the lesion had been there for approximately 19 years and had gotten progressively but not rapidly larger. Results of a physical examination revealed a 3-cm indurated hyperpigmented plaque with prominent scale (Figure 1). There were approximately 21 other lesions (of varying age by patient report); the most prominent lesion was located on the right shoulder (Figure 2). Other clinically similar lesions, ranging from less than 1 cm to about 10 cm, were noted on the hands, arms, shoulders, back, abdomen, thighs, and lower legs in both sun-exposed and non–sun-exposed areas. There were no lesions on the face.

Biopsy results revealed a microcystic adnexal carcinoma (MAC). Subsequent workup, including computed tomography, revealed 3 small areas of pleural thickening but no evidence of internal metastatic disease. The patient had no other significant medical history, and he reported no prior radiation therapy. He reported that none of his family members had a history of MAC. Eighteen months after the patient's lesions were first biopsied, no subsequent lesions had developed, and no substantial clinical progression of current lesions was noted; the patient remained in good health. Histology—Punch biopsy specimens were obtained of lesions in the upper left lateral thigh, lower left inner leg, and left web space between the thumb and index finger. An excisional specimen was available for the lesion from the left thigh. Biopsies of all 3 lesions showed similar histology (Figure 3). Examination results from the specimens at low power revealed mild to moderate psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and basilar hyperpigmentation, changes similarly encountered in lichen simplex chronicus. Larger cystic structures were immediately subadjacent in the superficial dermis, with follicular differentiation and cyst formation. Admixed were ductal structures consisting of basaloid cells, with eccrine differentiation consisting of cells with a moderate amount of pale ill-defined eosinophilic cytoplasm and oval hyperchromatic nuclei. Cytologic pleomorphism was not encountered.

Overall, the tumors demonstrated a stratified appearance, with larger cystic structures in the superficial dermis being replaced by smaller cysts and cords and nests of cells in the deeper dermis (Figure 4). In all specimens, there was extension into the subcutis. Perineural invasion was identified focally. In the superficial dermis of some of the specimens, the follicular cystic structures showed evidence of rupture, with keratin debris in the adjacent dermis and subsequent foreign body giant cell reaction. Results of immunoperoxidase tests on paraffin tissue showed the epithelial cells to be diffusely positive for cytokeratins (AE1/AE3) and carcinoembryonic antigen. Evaluations for the presence of estrogen and progesterone receptors both had negative results.

Comment
MAC is an uncommon adnexal malignancy with locally aggressive and infrequently metastatic behavior. Originally described by Goldstein et al,1 this lesion has a propensity for the centrofrontal area. Clinically, this neoplasm usually presents with an indurated plaque or nodule averaging 2 cm. MAC has been reported as long-standing in some patients, with an inclination for recurrence despite extensive surgical therapy. The lesions are infiltrative, and perineural invasion is frequent.2,3 Locoregional metastasis is an infrequent occurrence,4-8 and widespread metastasis has been described in only one case.9 Although MACs can arise in virtually any age group, most MACs occur in older individuals, with a reported average age of incidence between 44 and 64 years and an overall range of 11 to 90 years.3,10 Although a slight female predominance has been noted in some case series, overall the sexes are equally affected.11 A review of the cases of MAC in the slide files of our laboratory revealed a similar distribution, with an average age of 63 years and a 1:1 male-female ratio. Most of our cases also involved the face or neck, with this patient as the only case of MACs occurring elsewhere anatomically. The principle underlying risk factors for and etiologic influences of MAC are largely unknown. Several studies have noted that MACs are found predominantly on the left side of the face. The exact reason for this anatomic distribution is unclear, but it could be indicative of the fact that MAC has a tendency to develop in UV-exposed areas. A prior review has postulated that this distribution could be caused by sun exposure while driving; however, this theory has not been adequately tested because no comparisons have been made between incidence in the United States versus Australia or England where driving, and thereby sun exposure, occur on the right side.12 Prior radiation exposure also has been implicated as a potential risk factor, and several cases have described MAC occurring in an area of previous radiation therapy.13,14 Similarly, a potential explanation for a portion of these lesions occurring on the face is that several patients with MAC have had prior radiation therapy for facial acne.10,15 There also is a report in the literature of MACs occurring in the axilla in patients who received radiation therapy for breast cancer.3 Additionally, immunodeficiency has been implicated as an etiologic influence,4 and there is one report of documenting a familial influence with occurrence in 2 sisters.10 MAC is a rare tumor, and the lack of physician familiarity with it and limited biopsy sampling can frequently lead to misdiagnosis. As described in the current case, MAC clinically can present as a plaquelike, nodular, or cystlike tumor existing for many years and occasionally for decades. The overlying skin may appear unaffected or have slight lichenification, and ulceration is extremely uncommon. Often, the tumor is biopsied numerous times during several years before a correct diagnosis is made. As infrequent as MAC is, it is fleetingly rare in the black population. Only 3 case reports exist in the literature, and these lesions were all solitary.16-18 One of the cases was similar to ours in that the lesion was very large and long-standing; the lesion was present on the scalp for at least 31 years. The other 2 reported cases involved the scalp and upper lip, and the lesions in both cases were smaller than 2 cm.16-18 The histologic similarities of MAC with other basaloid tumors, combined with its indistinct clinical appearance, can lead to misdiagnosis. MACs typically demonstrate histology results similar to our case. The Table lists both benign and malignant tumors that share histologic features with MAC. The histologic features that are most helpful in distinguishing MAC from these benign and malignant entities are a stratified histologic appearance with ductal differentiation and the presence of perineural involvement with deep dermal infiltration. Although a desmoplastic trichoepithelioma will commonly show similar 2-tier histology results, with the presence of superficial keratocysts and a deeper basaloid infiltrative cell population, the condition will not have deep dermal involvement, ductal differentiation, or perineural involvement. Perineural involvement also will not be demonstrated in syringoma or trichoadenoma. Although deep dermal involvement and perineural invasion can be seen in the 3 malignant entities included in the Table, the histology results of these conditions typically will not show a stratified appearance. Basal cell carcinoma, in addition, rarely demonstrates ductal differentiation in the morpheic or infiltrative form.11

To our knowledge, no case reports of patients with multiple primary cutaneous lesions existed prior to the presentation of this patient. Martin et al¹⁹ describe an 8-year-old patient with multiple carcinomas on the lower extremities arising within systemized compound epithelial lesions; however, only one of these lesions was MAC, and the remainder showed divergent differentiation. Multiple primary lesions in our current case are manifested by the stratified histologic appearance of the tumor at the primary sites and are supported by the lack of metastatic disease elsewhere, which was demonstrated by extensive clinical examination and the absence of additional clinical symptoms or suspicious lesions on computed tomography. Reports of metastasis in MACs also are infrequent and represent only 6 cases in the medical literature worldwide3-5,7-9; 4 of these cases possibly do not describe true metastases3-5,7—one in the axilla that arguably represented tumor extension.3 Two of the others showed metastatic disease in ipsilateral lymph nodes, with a primary lesion on the right posterior scalp4 and the upper forehead,7 respectively. The fourth case illustrated cutaneous metastases in transit, possibly representing recurrence and not metastasis.5 A recent report described a patient with lung metastases,8 and a single case exists in the literature of a patient with widely metastatic MAC of long-standing duration.6 For this reason, and despite its aggressive local behavior, MAC is considered to be a tumor with excellent overall prognosis. Of the more than 300 cases from the medical literature worldwide, only the group of aforementioned lesions demonstrated metastatic potential, which represents an incidence rate of only 2% (probably overrepresented because reported cases only are a fraction of cases in existence). The death rate of reported cases, 0.3%, is an overestimate for similar reasons.21 Because MAC demonstrates its greatest morbidity from local invasion and destruction with locoregional recurrence, the optimal therapeutic approach generally consists of Mohs micrographic surgery (MMS) or primary surgical excision (intraoperative frozen section).12 Local recurrence following surgical excision, however, is not uncommon. In a comprehensive study using MMS, it was found that the extent of these lesions generally is 4-fold larger than the initially clinically evident lesion. Hence, intraoperative assessment of marginal status is paramount.12 In a study of 48 cases, 22 cases were treated with MMS, 23 cases were treated with simple excision, and 3 cases were untreated.12 Only 2 of the cases treated with MMS recurred after a single procedure. In those cases treated with excision, 7 cases (30%) had to have at least one additional surgical procedure before excision was deemed complete, and 1 case experienced recurrence. The overall recurrence rate was similar between the 2 groups (1.98% per patient-year), but fewer procedures were required.12 Although a small number of cases have been treated with adjuvant modalities, including radiation and chemotherapy, the effectiveness of this protocol, in addition to surgical excision, is most likely minimal.22 Our case represents a therapeutic problem in that the number and size of the lesions would be a monumental task to undertake surgically. The indolent course of these lesions might require a conservative clinical approach, such as surgical therapy reserved for problematic or aesthetically displeasing lesions. Systemic therapy was proposed in this patient, possibly using currently known biologic adjunctive therapy such as tamoxifen citrate and trastuzumab. Given that this tumor tested negative for both estrogen and progesterone receptors, as well as HER2/neu, biologic therapy was not undertaken. In addition, the indolent nature and low proliferative rate of these neoplasms most likely would make them poorly responsive to radiation or chemotherapy. A recent case report by Eisen and Zloty21 described a 58-year-old woman with a 12X12-cm MAC involving a large portion of the face. Similar to our case, this patient presented a difficult therapeutic problem because surgical intervention would involve substantial facial disfigurement. The authors opted, as we did, for close clinical surveillance; 2 years after initial diagnosis, the patient continued to do well, with no reported evidence of metastatic disease.21 Radiation therapy has been advocated for palliation in elderly or debilitated individuals; however, this therapy is less than ideal because these lesions generally are radioresistant, and recurrence following this therapy is not infrequent. In addition, radiation has been implicated as a causative mechanism. Comparing treatment methods for a tumor for which no randomized prospective studies exist is difficult, but because the tumor can be locally aggressive, surgical therapy should be pursued if feasible.

Comment
Our case of multiple primary cutaneous MAC in a black patient appears to represent a unique presentation of MAC. Therapeutic options, particularly in a patient with multiple lesions, represent a difficult clinical problem; however, close clinical follow-up without surgical intervention, except for those cases in which MMS is feasible, remains a reasonable alternative.

Microcystic adnexal carcinoma (MAC) is a relatively uncommon adnexal neoplasm that can demonstrate locally aggressive behavior; rare instances of metastatic lesions have been reported. We report a case of a 34-year-old black man with multiple primary MACs.

Case Report
An otherwise healthy 34-year-old black man presented for evaluation of a progressive lesion on the left thigh that had been diagnosed as lichen simplex chronicus 15 years earlier. The patient stated that the lesion had been there for approximately 19 years and had gotten progressively but not rapidly larger. Results of a physical examination revealed a 3-cm indurated hyperpigmented plaque with prominent scale (Figure 1). There were approximately 21 other lesions (of varying age by patient report); the most prominent lesion was located on the right shoulder (Figure 2). Other clinically similar lesions, ranging from less than 1 cm to about 10 cm, were noted on the hands, arms, shoulders, back, abdomen, thighs, and lower legs in both sun-exposed and non–sun-exposed areas. There were no lesions on the face.

Biopsy results revealed a microcystic adnexal carcinoma (MAC). Subsequent workup, including computed tomography, revealed 3 small areas of pleural thickening but no evidence of internal metastatic disease. The patient had no other significant medical history, and he reported no prior radiation therapy. He reported that none of his family members had a history of MAC. Eighteen months after the patient's lesions were first biopsied, no subsequent lesions had developed, and no substantial clinical progression of current lesions was noted; the patient remained in good health. Histology—Punch biopsy specimens were obtained of lesions in the upper left lateral thigh, lower left inner leg, and left web space between the thumb and index finger. An excisional specimen was available for the lesion from the left thigh. Biopsies of all 3 lesions showed similar histology (Figure 3). Examination results from the specimens at low power revealed mild to moderate psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and basilar hyperpigmentation, changes similarly encountered in lichen simplex chronicus. Larger cystic structures were immediately subadjacent in the superficial dermis, with follicular differentiation and cyst formation. Admixed were ductal structures consisting of basaloid cells, with eccrine differentiation consisting of cells with a moderate amount of pale ill-defined eosinophilic cytoplasm and oval hyperchromatic nuclei. Cytologic pleomorphism was not encountered.

Overall, the tumors demonstrated a stratified appearance, with larger cystic structures in the superficial dermis being replaced by smaller cysts and cords and nests of cells in the deeper dermis (Figure 4). In all specimens, there was extension into the subcutis. Perineural invasion was identified focally. In the superficial dermis of some of the specimens, the follicular cystic structures showed evidence of rupture, with keratin debris in the adjacent dermis and subsequent foreign body giant cell reaction. Results of immunoperoxidase tests on paraffin tissue showed the epithelial cells to be diffusely positive for cytokeratins (AE1/AE3) and carcinoembryonic antigen. Evaluations for the presence of estrogen and progesterone receptors both had negative results.

Comment
MAC is an uncommon adnexal malignancy with locally aggressive and infrequently metastatic behavior. Originally described by Goldstein et al,1 this lesion has a propensity for the centrofrontal area. Clinically, this neoplasm usually presents with an indurated plaque or nodule averaging 2 cm. MAC has been reported as long-standing in some patients, with an inclination for recurrence despite extensive surgical therapy. The lesions are infiltrative, and perineural invasion is frequent.2,3 Locoregional metastasis is an infrequent occurrence,4-8 and widespread metastasis has been described in only one case.9 Although MACs can arise in virtually any age group, most MACs occur in older individuals, with a reported average age of incidence between 44 and 64 years and an overall range of 11 to 90 years.3,10 Although a slight female predominance has been noted in some case series, overall the sexes are equally affected.11 A review of the cases of MAC in the slide files of our laboratory revealed a similar distribution, with an average age of 63 years and a 1:1 male-female ratio. Most of our cases also involved the face or neck, with this patient as the only case of MACs occurring elsewhere anatomically. The principle underlying risk factors for and etiologic influences of MAC are largely unknown. Several studies have noted that MACs are found predominantly on the left side of the face. The exact reason for this anatomic distribution is unclear, but it could be indicative of the fact that MAC has a tendency to develop in UV-exposed areas. A prior review has postulated that this distribution could be caused by sun exposure while driving; however, this theory has not been adequately tested because no comparisons have been made between incidence in the United States versus Australia or England where driving, and thereby sun exposure, occur on the right side.12 Prior radiation exposure also has been implicated as a potential risk factor, and several cases have described MAC occurring in an area of previous radiation therapy.13,14 Similarly, a potential explanation for a portion of these lesions occurring on the face is that several patients with MAC have had prior radiation therapy for facial acne.10,15 There also is a report in the literature of MACs occurring in the axilla in patients who received radiation therapy for breast cancer.3 Additionally, immunodeficiency has been implicated as an etiologic influence,4 and there is one report of documenting a familial influence with occurrence in 2 sisters.10 MAC is a rare tumor, and the lack of physician familiarity with it and limited biopsy sampling can frequently lead to misdiagnosis. As described in the current case, MAC clinically can present as a plaquelike, nodular, or cystlike tumor existing for many years and occasionally for decades. The overlying skin may appear unaffected or have slight lichenification, and ulceration is extremely uncommon. Often, the tumor is biopsied numerous times during several years before a correct diagnosis is made. As infrequent as MAC is, it is fleetingly rare in the black population. Only 3 case reports exist in the literature, and these lesions were all solitary.16-18 One of the cases was similar to ours in that the lesion was very large and long-standing; the lesion was present on the scalp for at least 31 years. The other 2 reported cases involved the scalp and upper lip, and the lesions in both cases were smaller than 2 cm.16-18 The histologic similarities of MAC with other basaloid tumors, combined with its indistinct clinical appearance, can lead to misdiagnosis. MACs typically demonstrate histology results similar to our case. The Table lists both benign and malignant tumors that share histologic features with MAC. The histologic features that are most helpful in distinguishing MAC from these benign and malignant entities are a stratified histologic appearance with ductal differentiation and the presence of perineural involvement with deep dermal infiltration. Although a desmoplastic trichoepithelioma will commonly show similar 2-tier histology results, with the presence of superficial keratocysts and a deeper basaloid infiltrative cell population, the condition will not have deep dermal involvement, ductal differentiation, or perineural involvement. Perineural involvement also will not be demonstrated in syringoma or trichoadenoma. Although deep dermal involvement and perineural invasion can be seen in the 3 malignant entities included in the Table, the histology results of these conditions typically will not show a stratified appearance. Basal cell carcinoma, in addition, rarely demonstrates ductal differentiation in the morpheic or infiltrative form.11

To our knowledge, no case reports of patients with multiple primary cutaneous lesions existed prior to the presentation of this patient. Martin et al¹⁹ describe an 8-year-old patient with multiple carcinomas on the lower extremities arising within systemized compound epithelial lesions; however, only one of these lesions was MAC, and the remainder showed divergent differentiation. Multiple primary lesions in our current case are manifested by the stratified histologic appearance of the tumor at the primary sites and are supported by the lack of metastatic disease elsewhere, which was demonstrated by extensive clinical examination and the absence of additional clinical symptoms or suspicious lesions on computed tomography. Reports of metastasis in MACs also are infrequent and represent only 6 cases in the medical literature worldwide3-5,7-9; 4 of these cases possibly do not describe true metastases3-5,7—one in the axilla that arguably represented tumor extension.3 Two of the others showed metastatic disease in ipsilateral lymph nodes, with a primary lesion on the right posterior scalp4 and the upper forehead,7 respectively. The fourth case illustrated cutaneous metastases in transit, possibly representing recurrence and not metastasis.5 A recent report described a patient with lung metastases,8 and a single case exists in the literature of a patient with widely metastatic MAC of long-standing duration.6 For this reason, and despite its aggressive local behavior, MAC is considered to be a tumor with excellent overall prognosis. Of the more than 300 cases from the medical literature worldwide, only the group of aforementioned lesions demonstrated metastatic potential, which represents an incidence rate of only 2% (probably overrepresented because reported cases only are a fraction of cases in existence). The death rate of reported cases, 0.3%, is an overestimate for similar reasons.21 Because MAC demonstrates its greatest morbidity from local invasion and destruction with locoregional recurrence, the optimal therapeutic approach generally consists of Mohs micrographic surgery (MMS) or primary surgical excision (intraoperative frozen section).12 Local recurrence following surgical excision, however, is not uncommon. In a comprehensive study using MMS, it was found that the extent of these lesions generally is 4-fold larger than the initially clinically evident lesion. Hence, intraoperative assessment of marginal status is paramount.12 In a study of 48 cases, 22 cases were treated with MMS, 23 cases were treated with simple excision, and 3 cases were untreated.12 Only 2 of the cases treated with MMS recurred after a single procedure. In those cases treated with excision, 7 cases (30%) had to have at least one additional surgical procedure before excision was deemed complete, and 1 case experienced recurrence. The overall recurrence rate was similar between the 2 groups (1.98% per patient-year), but fewer procedures were required.12 Although a small number of cases have been treated with adjuvant modalities, including radiation and chemotherapy, the effectiveness of this protocol, in addition to surgical excision, is most likely minimal.22 Our case represents a therapeutic problem in that the number and size of the lesions would be a monumental task to undertake surgically. The indolent course of these lesions might require a conservative clinical approach, such as surgical therapy reserved for problematic or aesthetically displeasing lesions. Systemic therapy was proposed in this patient, possibly using currently known biologic adjunctive therapy such as tamoxifen citrate and trastuzumab. Given that this tumor tested negative for both estrogen and progesterone receptors, as well as HER2/neu, biologic therapy was not undertaken. In addition, the indolent nature and low proliferative rate of these neoplasms most likely would make them poorly responsive to radiation or chemotherapy. A recent case report by Eisen and Zloty21 described a 58-year-old woman with a 12X12-cm MAC involving a large portion of the face. Similar to our case, this patient presented a difficult therapeutic problem because surgical intervention would involve substantial facial disfigurement. The authors opted, as we did, for close clinical surveillance; 2 years after initial diagnosis, the patient continued to do well, with no reported evidence of metastatic disease.21 Radiation therapy has been advocated for palliation in elderly or debilitated individuals; however, this therapy is less than ideal because these lesions generally are radioresistant, and recurrence following this therapy is not infrequent. In addition, radiation has been implicated as a causative mechanism. Comparing treatment methods for a tumor for which no randomized prospective studies exist is difficult, but because the tumor can be locally aggressive, surgical therapy should be pursued if feasible.

Comment
Our case of multiple primary cutaneous MAC in a black patient appears to represent a unique presentation of MAC. Therapeutic options, particularly in a patient with multiple lesions, represent a difficult clinical problem; however, close clinical follow-up without surgical intervention, except for those cases in which MMS is feasible, remains a reasonable alternative.

Microcystic adnexal carcinoma (MAC) is a relatively uncommon adnexal neoplasm that can demonstrate locally aggressive behavior; rare instances of metastatic lesions have been reported. We report a case of a 34-year-old black man with multiple primary MACs.

Case Report
An otherwise healthy 34-year-old black man presented for evaluation of a progressive lesion on the left thigh that had been diagnosed as lichen simplex chronicus 15 years earlier. The patient stated that the lesion had been there for approximately 19 years and had gotten progressively but not rapidly larger. Results of a physical examination revealed a 3-cm indurated hyperpigmented plaque with prominent scale (Figure 1). There were approximately 21 other lesions (of varying age by patient report); the most prominent lesion was located on the right shoulder (Figure 2). Other clinically similar lesions, ranging from less than 1 cm to about 10 cm, were noted on the hands, arms, shoulders, back, abdomen, thighs, and lower legs in both sun-exposed and non–sun-exposed areas. There were no lesions on the face.

Biopsy results revealed a microcystic adnexal carcinoma (MAC). Subsequent workup, including computed tomography, revealed 3 small areas of pleural thickening but no evidence of internal metastatic disease. The patient had no other significant medical history, and he reported no prior radiation therapy. He reported that none of his family members had a history of MAC. Eighteen months after the patient's lesions were first biopsied, no subsequent lesions had developed, and no substantial clinical progression of current lesions was noted; the patient remained in good health. Histology—Punch biopsy specimens were obtained of lesions in the upper left lateral thigh, lower left inner leg, and left web space between the thumb and index finger. An excisional specimen was available for the lesion from the left thigh. Biopsies of all 3 lesions showed similar histology (Figure 3). Examination results from the specimens at low power revealed mild to moderate psoriasiform epidermal hyperplasia with acanthosis, hyperkeratosis, and basilar hyperpigmentation, changes similarly encountered in lichen simplex chronicus. Larger cystic structures were immediately subadjacent in the superficial dermis, with follicular differentiation and cyst formation. Admixed were ductal structures consisting of basaloid cells, with eccrine differentiation consisting of cells with a moderate amount of pale ill-defined eosinophilic cytoplasm and oval hyperchromatic nuclei. Cytologic pleomorphism was not encountered.

Overall, the tumors demonstrated a stratified appearance, with larger cystic structures in the superficial dermis being replaced by smaller cysts and cords and nests of cells in the deeper dermis (Figure 4). In all specimens, there was extension into the subcutis. Perineural invasion was identified focally. In the superficial dermis of some of the specimens, the follicular cystic structures showed evidence of rupture, with keratin debris in the adjacent dermis and subsequent foreign body giant cell reaction. Results of immunoperoxidase tests on paraffin tissue showed the epithelial cells to be diffusely positive for cytokeratins (AE1/AE3) and carcinoembryonic antigen. Evaluations for the presence of estrogen and progesterone receptors both had negative results.

Comment
MAC is an uncommon adnexal malignancy with locally aggressive and infrequently metastatic behavior. Originally described by Goldstein et al,1 this lesion has a propensity for the centrofrontal area. Clinically, this neoplasm usually presents with an indurated plaque or nodule averaging 2 cm. MAC has been reported as long-standing in some patients, with an inclination for recurrence despite extensive surgical therapy. The lesions are infiltrative, and perineural invasion is frequent.2,3 Locoregional metastasis is an infrequent occurrence,4-8 and widespread metastasis has been described in only one case.9 Although MACs can arise in virtually any age group, most MACs occur in older individuals, with a reported average age of incidence between 44 and 64 years and an overall range of 11 to 90 years.3,10 Although a slight female predominance has been noted in some case series, overall the sexes are equally affected.11 A review of the cases of MAC in the slide files of our laboratory revealed a similar distribution, with an average age of 63 years and a 1:1 male-female ratio. Most of our cases also involved the face or neck, with this patient as the only case of MACs occurring elsewhere anatomically. The principle underlying risk factors for and etiologic influences of MAC are largely unknown. Several studies have noted that MACs are found predominantly on the left side of the face. The exact reason for this anatomic distribution is unclear, but it could be indicative of the fact that MAC has a tendency to develop in UV-exposed areas. A prior review has postulated that this distribution could be caused by sun exposure while driving; however, this theory has not been adequately tested because no comparisons have been made between incidence in the United States versus Australia or England where driving, and thereby sun exposure, occur on the right side.12 Prior radiation exposure also has been implicated as a potential risk factor, and several cases have described MAC occurring in an area of previous radiation therapy.13,14 Similarly, a potential explanation for a portion of these lesions occurring on the face is that several patients with MAC have had prior radiation therapy for facial acne.10,15 There also is a report in the literature of MACs occurring in the axilla in patients who received radiation therapy for breast cancer.3 Additionally, immunodeficiency has been implicated as an etiologic influence,4 and there is one report of documenting a familial influence with occurrence in 2 sisters.10 MAC is a rare tumor, and the lack of physician familiarity with it and limited biopsy sampling can frequently lead to misdiagnosis. As described in the current case, MAC clinically can present as a plaquelike, nodular, or cystlike tumor existing for many years and occasionally for decades. The overlying skin may appear unaffected or have slight lichenification, and ulceration is extremely uncommon. Often, the tumor is biopsied numerous times during several years before a correct diagnosis is made. As infrequent as MAC is, it is fleetingly rare in the black population. Only 3 case reports exist in the literature, and these lesions were all solitary.16-18 One of the cases was similar to ours in that the lesion was very large and long-standing; the lesion was present on the scalp for at least 31 years. The other 2 reported cases involved the scalp and upper lip, and the lesions in both cases were smaller than 2 cm.16-18 The histologic similarities of MAC with other basaloid tumors, combined with its indistinct clinical appearance, can lead to misdiagnosis. MACs typically demonstrate histology results similar to our case. The Table lists both benign and malignant tumors that share histologic features with MAC. The histologic features that are most helpful in distinguishing MAC from these benign and malignant entities are a stratified histologic appearance with ductal differentiation and the presence of perineural involvement with deep dermal infiltration. Although a desmoplastic trichoepithelioma will commonly show similar 2-tier histology results, with the presence of superficial keratocysts and a deeper basaloid infiltrative cell population, the condition will not have deep dermal involvement, ductal differentiation, or perineural involvement. Perineural involvement also will not be demonstrated in syringoma or trichoadenoma. Although deep dermal involvement and perineural invasion can be seen in the 3 malignant entities included in the Table, the histology results of these conditions typically will not show a stratified appearance. Basal cell carcinoma, in addition, rarely demonstrates ductal differentiation in the morpheic or infiltrative form.11

To our knowledge, no case reports of patients with multiple primary cutaneous lesions existed prior to the presentation of this patient. Martin et al¹⁹ describe an 8-year-old patient with multiple carcinomas on the lower extremities arising within systemized compound epithelial lesions; however, only one of these lesions was MAC, and the remainder showed divergent differentiation. Multiple primary lesions in our current case are manifested by the stratified histologic appearance of the tumor at the primary sites and are supported by the lack of metastatic disease elsewhere, which was demonstrated by extensive clinical examination and the absence of additional clinical symptoms or suspicious lesions on computed tomography. Reports of metastasis in MACs also are infrequent and represent only 6 cases in the medical literature worldwide3-5,7-9; 4 of these cases possibly do not describe true metastases3-5,7—one in the axilla that arguably represented tumor extension.3 Two of the others showed metastatic disease in ipsilateral lymph nodes, with a primary lesion on the right posterior scalp4 and the upper forehead,7 respectively. The fourth case illustrated cutaneous metastases in transit, possibly representing recurrence and not metastasis.5 A recent report described a patient with lung metastases,8 and a single case exists in the literature of a patient with widely metastatic MAC of long-standing duration.6 For this reason, and despite its aggressive local behavior, MAC is considered to be a tumor with excellent overall prognosis. Of the more than 300 cases from the medical literature worldwide, only the group of aforementioned lesions demonstrated metastatic potential, which represents an incidence rate of only 2% (probably overrepresented because reported cases only are a fraction of cases in existence). The death rate of reported cases, 0.3%, is an overestimate for similar reasons.21 Because MAC demonstrates its greatest morbidity from local invasion and destruction with locoregional recurrence, the optimal therapeutic approach generally consists of Mohs micrographic surgery (MMS) or primary surgical excision (intraoperative frozen section).12 Local recurrence following surgical excision, however, is not uncommon. In a comprehensive study using MMS, it was found that the extent of these lesions generally is 4-fold larger than the initially clinically evident lesion. Hence, intraoperative assessment of marginal status is paramount.12 In a study of 48 cases, 22 cases were treated with MMS, 23 cases were treated with simple excision, and 3 cases were untreated.12 Only 2 of the cases treated with MMS recurred after a single procedure. In those cases treated with excision, 7 cases (30%) had to have at least one additional surgical procedure before excision was deemed complete, and 1 case experienced recurrence. The overall recurrence rate was similar between the 2 groups (1.98% per patient-year), but fewer procedures were required.12 Although a small number of cases have been treated with adjuvant modalities, including radiation and chemotherapy, the effectiveness of this protocol, in addition to surgical excision, is most likely minimal.22 Our case represents a therapeutic problem in that the number and size of the lesions would be a monumental task to undertake surgically. The indolent course of these lesions might require a conservative clinical approach, such as surgical therapy reserved for problematic or aesthetically displeasing lesions. Systemic therapy was proposed in this patient, possibly using currently known biologic adjunctive therapy such as tamoxifen citrate and trastuzumab. Given that this tumor tested negative for both estrogen and progesterone receptors, as well as HER2/neu, biologic therapy was not undertaken. In addition, the indolent nature and low proliferative rate of these neoplasms most likely would make them poorly responsive to radiation or chemotherapy. A recent case report by Eisen and Zloty21 described a 58-year-old woman with a 12X12-cm MAC involving a large portion of the face. Similar to our case, this patient presented a difficult therapeutic problem because surgical intervention would involve substantial facial disfigurement. The authors opted, as we did, for close clinical surveillance; 2 years after initial diagnosis, the patient continued to do well, with no reported evidence of metastatic disease.21 Radiation therapy has been advocated for palliation in elderly or debilitated individuals; however, this therapy is less than ideal because these lesions generally are radioresistant, and recurrence following this therapy is not infrequent. In addition, radiation has been implicated as a causative mechanism. Comparing treatment methods for a tumor for which no randomized prospective studies exist is difficult, but because the tumor can be locally aggressive, surgical therapy should be pursued if feasible.

Comment
Our case of multiple primary cutaneous MAC in a black patient appears to represent a unique presentation of MAC. Therapeutic options, particularly in a patient with multiple lesions, represent a difficult clinical problem; however, close clinical follow-up without surgical intervention, except for those cases in which MMS is feasible, remains a reasonable alternative.

Prior to the 1980s, the term hemangioendothelioma (HE) loosely applied to a spectrum of vascular tumors ranging from benign tumors, such as capillary hemangiomas, to fully malignant angiosarcomas. In the early 1980s, the term epithelioid HE was used to describe a heterogeneous group of vascular tumors with an intermediate clinical course between hemangiomas and conventional angiosarcomas, thereby bringing to notice the borderline nature of these tumors. Since then, HEs have become a distinct entity, being further classified into spindle cell HE, retiform HE, kaposiform HE, and polymorphous HE. We present a case of spindle cell HE that began as an interdigital nodule and progressively became multifocal to involve the entire right upper extremity and chest wall, despite multiple surgical excisions, resulting in severe ongoing disfigurement of the patient.

Case Report
A 43-year-old woman presented with several painful nodules on her right arm, shoulder, and right side of the chest wall. When the patient was 5 years old, an isolated, small, nontender, flesh-colored nodule at the tip of the right index finger developed, which was thought to be a keloid. The lesion gradually grew, and multiple nodules appeared on her right hand and forearm. Despite multiple surgical excisions, the lesions not only continued to recur in operated sites but also progressed proximally to involve the entire right upper extremity as well as the right chest wall. Results of a physical examination revealed poorly demarcated nodules, less than 1 to 3 cm in diameter, some with a reddish-violet tinge but with no ulceration of the overlying skin (Figures 1 and 2). The nodules were soft, compressible, nonpulsatile, tender to palpation, and movable within the subcutaneous tissue. Port-wine stains and varicosities were noticeably absent. Hand function was mechanically compromised and wrist extension was very weak.

Fifteen years earlier, a radiograph of the patient's right hand demonstrated multiple soft tissue masses with multiple phleboliths (Figure 3); a biopsy specimen of the lesion examined at our hospital was interpreted as cavernous hemangioma. There were no such lesions elsewhere on the body. Results of radiographs of the right hand and forearm from the patient's current visit demonstrated multiple soft tissue masses with marked increase in the number of phleboliths but no bony growths or deformities (Figure 4). Results of an ultrasound examination did not show deep venous thrombosis. Results of magnetic resonance imaging of the right hand and forearm again revealed multiple soft tissue masses (Figure 5). Angiogram and tomogram results revealed pooling of blood in cavernous spaces of the soft tissue masses but no arteriovenous malformations (Figure 6). Findings from a surgical dissection revealed right forearm extensor tendon involvement. The surgical dissection was followed by excisional biopsy (with minimal healthy margins) and skin grafting.

Results of histologic examination 15 years prior revealed a poorly circumscribed dermis and subcutis, with thin-walled cavernous spaces containing focal areas of organizing thrombosis and spindle-shaped cells admixed with solid cellular components. At high power magnification, no mitotic activity was seen either in the endothelial or spindle cells. Despite multiple surgeries, embolizations, and radiation, the lesions continued to progress proximally, resulting in marked disfigurement of the involved extremity. The patient currently uses a custom surgical compression stocking for her right arm.

Comment
In 1982, Weiss and Enzinger1 were the first to use the term epithelioid hemangioendothelioma (HE). Spindle cell HE was first described by Weiss and Enzinger2 in 1986 and was characterized by the presence of thin-walled, cavernous, vascular spaces, some containing phleboliths, alternating with cellular stroma composed of spindled fibroblastic cells. Perkins and Weiss3 extensively evaluated 78 cases of spindle cell HE to reassess the lesion's biologic behavior. Males and females were found to be equally affected with a median age of onset of 32 years (range, 8—78 years).3 Patients with spindle cell HE typically present with slow growing, infiltrative, uninodular, or multinodular dermal or subcutaneous masses originating most commonly in the distal extremities, with a tendency to cluster in one region.3,4 The head, neck, chest, and abdomen also have been reported as primary sites of origin in a minority of cases.3 These masses often cause little or no discoloration of the overlying skin, which precludes identification as a vascular lesion, though reddish-brown discoloration observed in some patients can be suggestive of spindle cell HE.3,4 Patients often seek medical attention late, with a delay of 10 years or more in nearly one third of patients.3 Radiograph findings of spindle cell HEs can show phleboliths within circumscribed soft tissue masses, suggesting the vascular nature of these tumors. In our case, the notable absence of enchondromas distinguishes it from Maffucci syndrome, which is seen in approximately 5% of patients with spindle cell HE.3 The absence of port-wine stains, varicosities, and arteriovenous malformations differentiates our case from Klippel-Trenaunay syndrome and Klippel-Trenaunay-Weber syndrome. Histopathologic findings of these HE masses typically show 2 zones. The first zone is comprised of thin-walled cavernous spaces lined by flattened differentiated endothelial cells. These spaces either may be empty or filled with erythrocytes, thrombi, or phleboliths. The second zone typically consists of differentiated spindle-shaped fibroblastic cells interspersed by collapsed cavernous spaces, some areas with polygonal endothelial cells (epithelioid) and cytoplasmic vacuolation,3 which in our case, combined with a nonreactive human immunodeficiency virus test, differentiates it from Kaposi sarcoma. These spindle cells almost never contain significant nuclear atypia or mitotic activity. Because metastases have not been reported in association with spindle cell HE, except in one case that was believed to be radiation-induced sarcomatous transformation,3 the very introduction of this entity as a low-grade angiosarcoma has been questioned. It is now believed that spindle cell HE is most likely a benign reactive process that develops because of aberrations in local blood flow,3-6 which Perkins and Weiss3 have restudied and recommended that the entity be renamed spindle cell HE for solitary lesions and spindle cell hemangiomatosis for multifocal lesions. Treatment for these tumors should be conservative because of their benign clinical behavior. Several therapeutic approaches, including surgery, systemic steroids, cryotherapy, laser therapy, radiation therapy, cytotoxic drugs, and selective embolization, have been used.7 Recombinant interleukin 2, a T-cell derived lymphokine with immunologic functions (eg, induction of lymphokine-activated killer cells, augmentation of activities of cytotoxic T cells and natural killer cells), has been tried with success. Radiation therapy should be discouraged because of a report of sarcomatous transformation with subsequent metastasis.3,7 Clinical surveillance is mandatory with spindle cell HE and Maffucci syndrome because of increased risk of chondrosarcoma and other neoplasms.3 

Conclusion
Spindle cell HE is a rare vascular tumor of benign behavior that often starts as a soft tissue nodule in distal extremities that multiplies over time, with a tendency to cluster in one region. Patients often seek medical attention for cosmetic reasons and present late. Radiograph findings may demonstrate phleboliths, and an increase in the number of phleboliths may suggest progression, as seen in our case. Associated conditions include Maffucci, Klippel-Trenaunay, and Klippel-Trenaunay-Weber syndromes. Histologically, it is important to differentiate this entity from others that may assume a spindle appearance (eg, Kaposi sarcoma) or an epithelioid appearance (eg, metastatic carcinoma, various sarcomas). Although best treated with surgical resection, these tumors tend to have local and regional recurrence. Radiation therapy, as delivered in our case, should not be used because of the possibility of malignant transformation.

Prior to the 1980s, the term hemangioendothelioma (HE) loosely applied to a spectrum of vascular tumors ranging from benign tumors, such as capillary hemangiomas, to fully malignant angiosarcomas. In the early 1980s, the term epithelioid HE was used to describe a heterogeneous group of vascular tumors with an intermediate clinical course between hemangiomas and conventional angiosarcomas, thereby bringing to notice the borderline nature of these tumors. Since then, HEs have become a distinct entity, being further classified into spindle cell HE, retiform HE, kaposiform HE, and polymorphous HE. We present a case of spindle cell HE that began as an interdigital nodule and progressively became multifocal to involve the entire right upper extremity and chest wall, despite multiple surgical excisions, resulting in severe ongoing disfigurement of the patient.

Case Report
A 43-year-old woman presented with several painful nodules on her right arm, shoulder, and right side of the chest wall. When the patient was 5 years old, an isolated, small, nontender, flesh-colored nodule at the tip of the right index finger developed, which was thought to be a keloid. The lesion gradually grew, and multiple nodules appeared on her right hand and forearm. Despite multiple surgical excisions, the lesions not only continued to recur in operated sites but also progressed proximally to involve the entire right upper extremity as well as the right chest wall. Results of a physical examination revealed poorly demarcated nodules, less than 1 to 3 cm in diameter, some with a reddish-violet tinge but with no ulceration of the overlying skin (Figures 1 and 2). The nodules were soft, compressible, nonpulsatile, tender to palpation, and movable within the subcutaneous tissue. Port-wine stains and varicosities were noticeably absent. Hand function was mechanically compromised and wrist extension was very weak.

Fifteen years earlier, a radiograph of the patient's right hand demonstrated multiple soft tissue masses with multiple phleboliths (Figure 3); a biopsy specimen of the lesion examined at our hospital was interpreted as cavernous hemangioma. There were no such lesions elsewhere on the body. Results of radiographs of the right hand and forearm from the patient's current visit demonstrated multiple soft tissue masses with marked increase in the number of phleboliths but no bony growths or deformities (Figure 4). Results of an ultrasound examination did not show deep venous thrombosis. Results of magnetic resonance imaging of the right hand and forearm again revealed multiple soft tissue masses (Figure 5). Angiogram and tomogram results revealed pooling of blood in cavernous spaces of the soft tissue masses but no arteriovenous malformations (Figure 6). Findings from a surgical dissection revealed right forearm extensor tendon involvement. The surgical dissection was followed by excisional biopsy (with minimal healthy margins) and skin grafting.

Results of histologic examination 15 years prior revealed a poorly circumscribed dermis and subcutis, with thin-walled cavernous spaces containing focal areas of organizing thrombosis and spindle-shaped cells admixed with solid cellular components. At high power magnification, no mitotic activity was seen either in the endothelial or spindle cells. Despite multiple surgeries, embolizations, and radiation, the lesions continued to progress proximally, resulting in marked disfigurement of the involved extremity. The patient currently uses a custom surgical compression stocking for her right arm.

Comment
In 1982, Weiss and Enzinger1 were the first to use the term epithelioid hemangioendothelioma (HE). Spindle cell HE was first described by Weiss and Enzinger2 in 1986 and was characterized by the presence of thin-walled, cavernous, vascular spaces, some containing phleboliths, alternating with cellular stroma composed of spindled fibroblastic cells. Perkins and Weiss3 extensively evaluated 78 cases of spindle cell HE to reassess the lesion's biologic behavior. Males and females were found to be equally affected with a median age of onset of 32 years (range, 8—78 years).3 Patients with spindle cell HE typically present with slow growing, infiltrative, uninodular, or multinodular dermal or subcutaneous masses originating most commonly in the distal extremities, with a tendency to cluster in one region.3,4 The head, neck, chest, and abdomen also have been reported as primary sites of origin in a minority of cases.3 These masses often cause little or no discoloration of the overlying skin, which precludes identification as a vascular lesion, though reddish-brown discoloration observed in some patients can be suggestive of spindle cell HE.3,4 Patients often seek medical attention late, with a delay of 10 years or more in nearly one third of patients.3 Radiograph findings of spindle cell HEs can show phleboliths within circumscribed soft tissue masses, suggesting the vascular nature of these tumors. In our case, the notable absence of enchondromas distinguishes it from Maffucci syndrome, which is seen in approximately 5% of patients with spindle cell HE.3 The absence of port-wine stains, varicosities, and arteriovenous malformations differentiates our case from Klippel-Trenaunay syndrome and Klippel-Trenaunay-Weber syndrome. Histopathologic findings of these HE masses typically show 2 zones. The first zone is comprised of thin-walled cavernous spaces lined by flattened differentiated endothelial cells. These spaces either may be empty or filled with erythrocytes, thrombi, or phleboliths. The second zone typically consists of differentiated spindle-shaped fibroblastic cells interspersed by collapsed cavernous spaces, some areas with polygonal endothelial cells (epithelioid) and cytoplasmic vacuolation,3 which in our case, combined with a nonreactive human immunodeficiency virus test, differentiates it from Kaposi sarcoma. These spindle cells almost never contain significant nuclear atypia or mitotic activity. Because metastases have not been reported in association with spindle cell HE, except in one case that was believed to be radiation-induced sarcomatous transformation,3 the very introduction of this entity as a low-grade angiosarcoma has been questioned. It is now believed that spindle cell HE is most likely a benign reactive process that develops because of aberrations in local blood flow,3-6 which Perkins and Weiss3 have restudied and recommended that the entity be renamed spindle cell HE for solitary lesions and spindle cell hemangiomatosis for multifocal lesions. Treatment for these tumors should be conservative because of their benign clinical behavior. Several therapeutic approaches, including surgery, systemic steroids, cryotherapy, laser therapy, radiation therapy, cytotoxic drugs, and selective embolization, have been used.7 Recombinant interleukin 2, a T-cell derived lymphokine with immunologic functions (eg, induction of lymphokine-activated killer cells, augmentation of activities of cytotoxic T cells and natural killer cells), has been tried with success. Radiation therapy should be discouraged because of a report of sarcomatous transformation with subsequent metastasis.3,7 Clinical surveillance is mandatory with spindle cell HE and Maffucci syndrome because of increased risk of chondrosarcoma and other neoplasms.3 

Conclusion
Spindle cell HE is a rare vascular tumor of benign behavior that often starts as a soft tissue nodule in distal extremities that multiplies over time, with a tendency to cluster in one region. Patients often seek medical attention for cosmetic reasons and present late. Radiograph findings may demonstrate phleboliths, and an increase in the number of phleboliths may suggest progression, as seen in our case. Associated conditions include Maffucci, Klippel-Trenaunay, and Klippel-Trenaunay-Weber syndromes. Histologically, it is important to differentiate this entity from others that may assume a spindle appearance (eg, Kaposi sarcoma) or an epithelioid appearance (eg, metastatic carcinoma, various sarcomas). Although best treated with surgical resection, these tumors tend to have local and regional recurrence. Radiation therapy, as delivered in our case, should not be used because of the possibility of malignant transformation.

Prior to the 1980s, the term hemangioendothelioma (HE) loosely applied to a spectrum of vascular tumors ranging from benign tumors, such as capillary hemangiomas, to fully malignant angiosarcomas. In the early 1980s, the term epithelioid HE was used to describe a heterogeneous group of vascular tumors with an intermediate clinical course between hemangiomas and conventional angiosarcomas, thereby bringing to notice the borderline nature of these tumors. Since then, HEs have become a distinct entity, being further classified into spindle cell HE, retiform HE, kaposiform HE, and polymorphous HE. We present a case of spindle cell HE that began as an interdigital nodule and progressively became multifocal to involve the entire right upper extremity and chest wall, despite multiple surgical excisions, resulting in severe ongoing disfigurement of the patient.

Case Report
A 43-year-old woman presented with several painful nodules on her right arm, shoulder, and right side of the chest wall. When the patient was 5 years old, an isolated, small, nontender, flesh-colored nodule at the tip of the right index finger developed, which was thought to be a keloid. The lesion gradually grew, and multiple nodules appeared on her right hand and forearm. Despite multiple surgical excisions, the lesions not only continued to recur in operated sites but also progressed proximally to involve the entire right upper extremity as well as the right chest wall. Results of a physical examination revealed poorly demarcated nodules, less than 1 to 3 cm in diameter, some with a reddish-violet tinge but with no ulceration of the overlying skin (Figures 1 and 2). The nodules were soft, compressible, nonpulsatile, tender to palpation, and movable within the subcutaneous tissue. Port-wine stains and varicosities were noticeably absent. Hand function was mechanically compromised and wrist extension was very weak.

Fifteen years earlier, a radiograph of the patient's right hand demonstrated multiple soft tissue masses with multiple phleboliths (Figure 3); a biopsy specimen of the lesion examined at our hospital was interpreted as cavernous hemangioma. There were no such lesions elsewhere on the body. Results of radiographs of the right hand and forearm from the patient's current visit demonstrated multiple soft tissue masses with marked increase in the number of phleboliths but no bony growths or deformities (Figure 4). Results of an ultrasound examination did not show deep venous thrombosis. Results of magnetic resonance imaging of the right hand and forearm again revealed multiple soft tissue masses (Figure 5). Angiogram and tomogram results revealed pooling of blood in cavernous spaces of the soft tissue masses but no arteriovenous malformations (Figure 6). Findings from a surgical dissection revealed right forearm extensor tendon involvement. The surgical dissection was followed by excisional biopsy (with minimal healthy margins) and skin grafting.

Results of histologic examination 15 years prior revealed a poorly circumscribed dermis and subcutis, with thin-walled cavernous spaces containing focal areas of organizing thrombosis and spindle-shaped cells admixed with solid cellular components. At high power magnification, no mitotic activity was seen either in the endothelial or spindle cells. Despite multiple surgeries, embolizations, and radiation, the lesions continued to progress proximally, resulting in marked disfigurement of the involved extremity. The patient currently uses a custom surgical compression stocking for her right arm.

Comment
In 1982, Weiss and Enzinger1 were the first to use the term epithelioid hemangioendothelioma (HE). Spindle cell HE was first described by Weiss and Enzinger2 in 1986 and was characterized by the presence of thin-walled, cavernous, vascular spaces, some containing phleboliths, alternating with cellular stroma composed of spindled fibroblastic cells. Perkins and Weiss3 extensively evaluated 78 cases of spindle cell HE to reassess the lesion's biologic behavior. Males and females were found to be equally affected with a median age of onset of 32 years (range, 8—78 years).3 Patients with spindle cell HE typically present with slow growing, infiltrative, uninodular, or multinodular dermal or subcutaneous masses originating most commonly in the distal extremities, with a tendency to cluster in one region.3,4 The head, neck, chest, and abdomen also have been reported as primary sites of origin in a minority of cases.3 These masses often cause little or no discoloration of the overlying skin, which precludes identification as a vascular lesion, though reddish-brown discoloration observed in some patients can be suggestive of spindle cell HE.3,4 Patients often seek medical attention late, with a delay of 10 years or more in nearly one third of patients.3 Radiograph findings of spindle cell HEs can show phleboliths within circumscribed soft tissue masses, suggesting the vascular nature of these tumors. In our case, the notable absence of enchondromas distinguishes it from Maffucci syndrome, which is seen in approximately 5% of patients with spindle cell HE.3 The absence of port-wine stains, varicosities, and arteriovenous malformations differentiates our case from Klippel-Trenaunay syndrome and Klippel-Trenaunay-Weber syndrome. Histopathologic findings of these HE masses typically show 2 zones. The first zone is comprised of thin-walled cavernous spaces lined by flattened differentiated endothelial cells. These spaces either may be empty or filled with erythrocytes, thrombi, or phleboliths. The second zone typically consists of differentiated spindle-shaped fibroblastic cells interspersed by collapsed cavernous spaces, some areas with polygonal endothelial cells (epithelioid) and cytoplasmic vacuolation,3 which in our case, combined with a nonreactive human immunodeficiency virus test, differentiates it from Kaposi sarcoma. These spindle cells almost never contain significant nuclear atypia or mitotic activity. Because metastases have not been reported in association with spindle cell HE, except in one case that was believed to be radiation-induced sarcomatous transformation,3 the very introduction of this entity as a low-grade angiosarcoma has been questioned. It is now believed that spindle cell HE is most likely a benign reactive process that develops because of aberrations in local blood flow,3-6 which Perkins and Weiss3 have restudied and recommended that the entity be renamed spindle cell HE for solitary lesions and spindle cell hemangiomatosis for multifocal lesions. Treatment for these tumors should be conservative because of their benign clinical behavior. Several therapeutic approaches, including surgery, systemic steroids, cryotherapy, laser therapy, radiation therapy, cytotoxic drugs, and selective embolization, have been used.7 Recombinant interleukin 2, a T-cell derived lymphokine with immunologic functions (eg, induction of lymphokine-activated killer cells, augmentation of activities of cytotoxic T cells and natural killer cells), has been tried with success. Radiation therapy should be discouraged because of a report of sarcomatous transformation with subsequent metastasis.3,7 Clinical surveillance is mandatory with spindle cell HE and Maffucci syndrome because of increased risk of chondrosarcoma and other neoplasms.3 

Conclusion
Spindle cell HE is a rare vascular tumor of benign behavior that often starts as a soft tissue nodule in distal extremities that multiplies over time, with a tendency to cluster in one region. Patients often seek medical attention for cosmetic reasons and present late. Radiograph findings may demonstrate phleboliths, and an increase in the number of phleboliths may suggest progression, as seen in our case. Associated conditions include Maffucci, Klippel-Trenaunay, and Klippel-Trenaunay-Weber syndromes. Histologically, it is important to differentiate this entity from others that may assume a spindle appearance (eg, Kaposi sarcoma) or an epithelioid appearance (eg, metastatic carcinoma, various sarcomas). Although best treated with surgical resection, these tumors tend to have local and regional recurrence. Radiation therapy, as delivered in our case, should not be used because of the possibility of malignant transformation.

Inflammatory linear verrucous epidermal nevus (ILVEN) is a unilateral, persistent, linear, pruritic eruption that usually appears on an extremity in infancy or childhood. We present a case of ILVEN in a 4-year-old boy and provide a short review of the literature, with emphasis on our current understanding of the etiology, clinical presentation, diagnosis, and management of ILVEN.

Case Report
A 4-year-old boy presented for evaluation of an extremely pruritic linear plaque involving his right groin and right thigh since the age of one year (Figure 1). The plaque first appeared on the right buttock (Figure 2) and slowly enlarged, extending down spirally to involve the right inguinal region and upper inner thigh. There was no family history of similar dermatoses.

Results of a physical examination revealed multiple erythematous warty scaling papules coalesced to form a linear, verrucous, hyperpigmented plaque. The plaque extended from the right buttock and inguinal region to the right upper medial thigh following the lines of Blaschko. The rest of the physical examination results were unremarkable, and no associated physical anomaly was found. The eruption and the associated pruritus did not respond to either oral antihistamines or topical high potency steroids. Results of a biopsy specimen taken from the lesion revealed hyperkeratosis, parakeratosis, acanthosis, and a decreased granular layer. A perivascular infiltrate of lymphocytes also was evident in the upper dermis. A diagnosis of inflammatory linear verrucous epidermal nevus (ILVEN) was made based on clinical and histopathologic grounds.

Comment
The condition later known as ILVEN was first described by Unna in 1896.1 However, it was not until 1971 that the disorder was described and clearly defined as a distinct entity by Altman and Mehregan2 in a case series of 25 patients. The authors clearly delineated ILVEN as a clinical and histopathologic variety of linear verrucous nevus that clinically appears inflammatory and histopathologically appears psoriasiform. The etiology of ILVEN remains unknown. It is considered a variant of keratinocytic epidermal nevus. Most cases are sporadic, but a familial case, with the condition occurring in a mother and her daughter, has been described.3 Because ILVEN bears some histologic resemblance to psoriasis, some authors believe that the 2 conditions share a common pathogenesis, possibly mediated by cytokines.4 There is some evidence that interleukins 1 and 6, tumor necrosis factor α, and intercellular adhesion molecule-1 are upregulated in ILVEN, similar to psoriasis.4 It also has been proposed that activation of an autosomal-dominant lethal mutation that survives by mosaicism may be the cause. The mutated cells might survive in the vicinity of the normal cells.5 ILVEN usually appears in infancy or early childhood but may be present at birth; the condition is very rarely present in adulthood.6 ILVEN occurs predominantly in females (female-male ratio, 4:1), and no racial predominance has been noted. About 6% of patients with epidermal nevi had ILVEN.6 ILVEN typically presents with multiple, discrete, erythematous, slightly warty and scaly papules that tend to coalesce into linear plaques. In a retrospective study of 23 patients with ILVEN, Lee and Rogers7 documented a predilection for the buttock and legs, and most cases were unilateral. Onset usually was within the first 6 months of life, most patients (16 patients) were male, and extension beyond the original margins occurred in 6 patients (26%).7 Altman and Mehregan² described 6 characteristic features of ILVEN: (1) early age of onset, (2) predominance in females (4:1 female-male ratio), (3) frequent involvement of the left leg, (4) pruritus, (5) marked refractoriness to therapy, and (6) a distinctive psoriasiform and inflammatory histologic appearance. In a few children, ILVEN has been found to occur in association with musculoskeletal or other abnormalities, including supernumerary digits and strabismus,8 congenital bony anomalies of the ipsilateral extremities,9 congenital dislocation of the ipsilateral hip and Fallot tetralogy of the heart,10 autoimmune thyroiditis,11 lichen amyloidosis,12 nevus depigmentosus,13 arthritis14 and melanodontia.15 More recently, ILVEN was associated with ipsilateral undescended testicle.16 However, this finding was disputed by Happle,17 who interpreted the case as an epidermal nevus of the epidermolytic type and stated that the ipsilateral cryptorchidism should be considered as a coincidental finding. The histopathologic presentation of ILVEN is very similar to psoriasis. Results of a histologic examination reveal psoriasiform hyperplasia of the epidermis, alternating parakeratosis without a granular layer, and orthokeratosis with a thickened granular layer.18 The authors of a recent study19 looked at advanced immunohistochemical methods to differentiate ILVEN from psoriasis. The investigators found that the number of Ki-67—positive nuclei tends to be lower, and the number of keratin-10—positive cells and HLA-DR expression tend to be higher in patients with ILVEN. The density of CD8+, CD45RO+, CD2+, CD94, and CD161 also showed a marked difference between ILVEN and psoriasis. In addition, the number of T cells relevant in the pathogenesis of psoriasis was markedly reduced in ILVEN.19 Other dermatoses that need to be differentiated from ILVEN are summarized in the Table. Nevoid psoriasis in a Blaschko distribution closely mimics ILVEN, but the former usually is asymptomatic and responds well to antipsoriatic treatment. Psoriasis also may become superimposed on an epidermal nevus because of Köbnerization.20

Epidermal nevi may occur almost anywhere on the head, neck, legs, or trunk.6 Nevus verrucosus is a term for the localized lesions of epidermal nevi.21 Linear verrucous epidermal nevi are linear hamartomas of epidermal structures that usually appear at birth or during infancy. Linear verrucous epidermal nevi usually are found on the lower extremities and have resistance to treatment and risk of recurrence. The nevi rarely are seen on the face and very rarely involve the oral mucosa.21 Clinically, there is no erythema or pruritus. Immunohistochemical studies further help differentiate ILVEN from other noninflammatory linear epidermal nevi. The CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) is characterized by segmentally distributed asymptomatic erythematous verrucous areas, associated with ipsilateral extremity defects, ranging from digital hypoplasia to agenesis of the extremity.22 Hence, ILVEN reported in association with severe extremity defects is most likely CHILD syndrome.23 An alternative acronym that has been used to describe this association is PENCIL (psoriasiform epidermal nevus with congenital ipsilateral limb defects).24 Lichen striatus usually is asymptomatic and resolves spontaneously. There also are histologic differences between ILVEN and lichen striatus.25 Linear lichen planus mainly affects children and is characterized by discrete pruritic, polygonal, violaceous papules arranged in a linear fashion, usually along an entire extremity; however, the papules also may be zosteriform.26 Linear porokeratosis also usually presents during childhood as ringlike, hypertrophic, verrucous plaques with a linear morphology, usually on a single extremity, but other parts of the body also may be involved.27 More recently, Jang et al28 reported a case of mycosis fungoides, presenting with a clinical picture of ILVEN. Nevoid basal cell carcinoma (BCC) syndrome is characterized by BCCs in both sun-exposed and nonexposed skin. The diameter of the lesions varies from 1 to 10 mm and commonly involves the face, back, and chest. Features such as odontogenic cysts, palmar and plantar pitting, and facial milia may be associated. Basaloid follicular hamartoma, also known as linear unilateral basal cell nevus with comedones, may present as a unilateral linear lesion.29 In its early stages, the lesion shows hypopigmented smooth or striaelike areas, which later may develop darker-pigmented papules and tumors with or without ulceration. Of note, it may be histologically indistinguishable from the infundibulocystic type of BCC.29 The most widely applied medical treatments for ILVEN have been intralesional corticosteroids or potent topical corticosteroids, the latter often with occlusion.30 However, the clinical appearance and associated intense pruritus usually are refractory to treatment. Topical calcipotriol has been reported to provide some relief in some patients,31 but it is not recommended in children because of limited clinical safety data. A recent case report noted improvement of pruritus in ILVEN with topical pimecrolimus cream.32 Dithranol has been used with success in one case report,33 but this has been interpreted as an antipsoriatic effect in ILVEN with superimposed psoriasis.34 Other therapeutic choices reported in the literature include topical tretinoin combined with 5-fluorouracil,35 and acitretin.36 Destructive therapies, such as the application of liquid nitrogen, electrodesiccation, ablative laser and dermabrasion, have all been equally disappointing.37 Of note, case reports have shown efficacy of CO238 and pulsed dye laser treatment.39 

Conclusion
ILVEN may be an isolated finding or may be associated with other abnormalities. Most patients pre-sent in infancy or early childhood. The diagnosis may sometimes be difficult and necessitate biopsy and advanced immunohistochemical analysis. Most lesions do not persist and spontaneously resolve by adulthood.40 The management usually is only symptomatic and often unsatisfactory. 

Inflammatory linear verrucous epidermal nevus (ILVEN) is a unilateral, persistent, linear, pruritic eruption that usually appears on an extremity in infancy or childhood. We present a case of ILVEN in a 4-year-old boy and provide a short review of the literature, with emphasis on our current understanding of the etiology, clinical presentation, diagnosis, and management of ILVEN.

Case Report
A 4-year-old boy presented for evaluation of an extremely pruritic linear plaque involving his right groin and right thigh since the age of one year (Figure 1). The plaque first appeared on the right buttock (Figure 2) and slowly enlarged, extending down spirally to involve the right inguinal region and upper inner thigh. There was no family history of similar dermatoses.

Results of a physical examination revealed multiple erythematous warty scaling papules coalesced to form a linear, verrucous, hyperpigmented plaque. The plaque extended from the right buttock and inguinal region to the right upper medial thigh following the lines of Blaschko. The rest of the physical examination results were unremarkable, and no associated physical anomaly was found. The eruption and the associated pruritus did not respond to either oral antihistamines or topical high potency steroids. Results of a biopsy specimen taken from the lesion revealed hyperkeratosis, parakeratosis, acanthosis, and a decreased granular layer. A perivascular infiltrate of lymphocytes also was evident in the upper dermis. A diagnosis of inflammatory linear verrucous epidermal nevus (ILVEN) was made based on clinical and histopathologic grounds.

Comment
The condition later known as ILVEN was first described by Unna in 1896.1 However, it was not until 1971 that the disorder was described and clearly defined as a distinct entity by Altman and Mehregan2 in a case series of 25 patients. The authors clearly delineated ILVEN as a clinical and histopathologic variety of linear verrucous nevus that clinically appears inflammatory and histopathologically appears psoriasiform. The etiology of ILVEN remains unknown. It is considered a variant of keratinocytic epidermal nevus. Most cases are sporadic, but a familial case, with the condition occurring in a mother and her daughter, has been described.3 Because ILVEN bears some histologic resemblance to psoriasis, some authors believe that the 2 conditions share a common pathogenesis, possibly mediated by cytokines.4 There is some evidence that interleukins 1 and 6, tumor necrosis factor α, and intercellular adhesion molecule-1 are upregulated in ILVEN, similar to psoriasis.4 It also has been proposed that activation of an autosomal-dominant lethal mutation that survives by mosaicism may be the cause. The mutated cells might survive in the vicinity of the normal cells.5 ILVEN usually appears in infancy or early childhood but may be present at birth; the condition is very rarely present in adulthood.6 ILVEN occurs predominantly in females (female-male ratio, 4:1), and no racial predominance has been noted. About 6% of patients with epidermal nevi had ILVEN.6 ILVEN typically presents with multiple, discrete, erythematous, slightly warty and scaly papules that tend to coalesce into linear plaques. In a retrospective study of 23 patients with ILVEN, Lee and Rogers7 documented a predilection for the buttock and legs, and most cases were unilateral. Onset usually was within the first 6 months of life, most patients (16 patients) were male, and extension beyond the original margins occurred in 6 patients (26%).7 Altman and Mehregan² described 6 characteristic features of ILVEN: (1) early age of onset, (2) predominance in females (4:1 female-male ratio), (3) frequent involvement of the left leg, (4) pruritus, (5) marked refractoriness to therapy, and (6) a distinctive psoriasiform and inflammatory histologic appearance. In a few children, ILVEN has been found to occur in association with musculoskeletal or other abnormalities, including supernumerary digits and strabismus,8 congenital bony anomalies of the ipsilateral extremities,9 congenital dislocation of the ipsilateral hip and Fallot tetralogy of the heart,10 autoimmune thyroiditis,11 lichen amyloidosis,12 nevus depigmentosus,13 arthritis14 and melanodontia.15 More recently, ILVEN was associated with ipsilateral undescended testicle.16 However, this finding was disputed by Happle,17 who interpreted the case as an epidermal nevus of the epidermolytic type and stated that the ipsilateral cryptorchidism should be considered as a coincidental finding. The histopathologic presentation of ILVEN is very similar to psoriasis. Results of a histologic examination reveal psoriasiform hyperplasia of the epidermis, alternating parakeratosis without a granular layer, and orthokeratosis with a thickened granular layer.18 The authors of a recent study19 looked at advanced immunohistochemical methods to differentiate ILVEN from psoriasis. The investigators found that the number of Ki-67—positive nuclei tends to be lower, and the number of keratin-10—positive cells and HLA-DR expression tend to be higher in patients with ILVEN. The density of CD8+, CD45RO+, CD2+, CD94, and CD161 also showed a marked difference between ILVEN and psoriasis. In addition, the number of T cells relevant in the pathogenesis of psoriasis was markedly reduced in ILVEN.19 Other dermatoses that need to be differentiated from ILVEN are summarized in the Table. Nevoid psoriasis in a Blaschko distribution closely mimics ILVEN, but the former usually is asymptomatic and responds well to antipsoriatic treatment. Psoriasis also may become superimposed on an epidermal nevus because of Köbnerization.20

Epidermal nevi may occur almost anywhere on the head, neck, legs, or trunk.6 Nevus verrucosus is a term for the localized lesions of epidermal nevi.21 Linear verrucous epidermal nevi are linear hamartomas of epidermal structures that usually appear at birth or during infancy. Linear verrucous epidermal nevi usually are found on the lower extremities and have resistance to treatment and risk of recurrence. The nevi rarely are seen on the face and very rarely involve the oral mucosa.21 Clinically, there is no erythema or pruritus. Immunohistochemical studies further help differentiate ILVEN from other noninflammatory linear epidermal nevi. The CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) is characterized by segmentally distributed asymptomatic erythematous verrucous areas, associated with ipsilateral extremity defects, ranging from digital hypoplasia to agenesis of the extremity.22 Hence, ILVEN reported in association with severe extremity defects is most likely CHILD syndrome.23 An alternative acronym that has been used to describe this association is PENCIL (psoriasiform epidermal nevus with congenital ipsilateral limb defects).24 Lichen striatus usually is asymptomatic and resolves spontaneously. There also are histologic differences between ILVEN and lichen striatus.25 Linear lichen planus mainly affects children and is characterized by discrete pruritic, polygonal, violaceous papules arranged in a linear fashion, usually along an entire extremity; however, the papules also may be zosteriform.26 Linear porokeratosis also usually presents during childhood as ringlike, hypertrophic, verrucous plaques with a linear morphology, usually on a single extremity, but other parts of the body also may be involved.27 More recently, Jang et al28 reported a case of mycosis fungoides, presenting with a clinical picture of ILVEN. Nevoid basal cell carcinoma (BCC) syndrome is characterized by BCCs in both sun-exposed and nonexposed skin. The diameter of the lesions varies from 1 to 10 mm and commonly involves the face, back, and chest. Features such as odontogenic cysts, palmar and plantar pitting, and facial milia may be associated. Basaloid follicular hamartoma, also known as linear unilateral basal cell nevus with comedones, may present as a unilateral linear lesion.29 In its early stages, the lesion shows hypopigmented smooth or striaelike areas, which later may develop darker-pigmented papules and tumors with or without ulceration. Of note, it may be histologically indistinguishable from the infundibulocystic type of BCC.29 The most widely applied medical treatments for ILVEN have been intralesional corticosteroids or potent topical corticosteroids, the latter often with occlusion.30 However, the clinical appearance and associated intense pruritus usually are refractory to treatment. Topical calcipotriol has been reported to provide some relief in some patients,31 but it is not recommended in children because of limited clinical safety data. A recent case report noted improvement of pruritus in ILVEN with topical pimecrolimus cream.32 Dithranol has been used with success in one case report,33 but this has been interpreted as an antipsoriatic effect in ILVEN with superimposed psoriasis.34 Other therapeutic choices reported in the literature include topical tretinoin combined with 5-fluorouracil,35 and acitretin.36 Destructive therapies, such as the application of liquid nitrogen, electrodesiccation, ablative laser and dermabrasion, have all been equally disappointing.37 Of note, case reports have shown efficacy of CO238 and pulsed dye laser treatment.39 

Conclusion
ILVEN may be an isolated finding or may be associated with other abnormalities. Most patients pre-sent in infancy or early childhood. The diagnosis may sometimes be difficult and necessitate biopsy and advanced immunohistochemical analysis. Most lesions do not persist and spontaneously resolve by adulthood.40 The management usually is only symptomatic and often unsatisfactory. 

Inflammatory linear verrucous epidermal nevus (ILVEN) is a unilateral, persistent, linear, pruritic eruption that usually appears on an extremity in infancy or childhood. We present a case of ILVEN in a 4-year-old boy and provide a short review of the literature, with emphasis on our current understanding of the etiology, clinical presentation, diagnosis, and management of ILVEN.

Case Report
A 4-year-old boy presented for evaluation of an extremely pruritic linear plaque involving his right groin and right thigh since the age of one year (Figure 1). The plaque first appeared on the right buttock (Figure 2) and slowly enlarged, extending down spirally to involve the right inguinal region and upper inner thigh. There was no family history of similar dermatoses.

Results of a physical examination revealed multiple erythematous warty scaling papules coalesced to form a linear, verrucous, hyperpigmented plaque. The plaque extended from the right buttock and inguinal region to the right upper medial thigh following the lines of Blaschko. The rest of the physical examination results were unremarkable, and no associated physical anomaly was found. The eruption and the associated pruritus did not respond to either oral antihistamines or topical high potency steroids. Results of a biopsy specimen taken from the lesion revealed hyperkeratosis, parakeratosis, acanthosis, and a decreased granular layer. A perivascular infiltrate of lymphocytes also was evident in the upper dermis. A diagnosis of inflammatory linear verrucous epidermal nevus (ILVEN) was made based on clinical and histopathologic grounds.

Comment
The condition later known as ILVEN was first described by Unna in 1896.1 However, it was not until 1971 that the disorder was described and clearly defined as a distinct entity by Altman and Mehregan2 in a case series of 25 patients. The authors clearly delineated ILVEN as a clinical and histopathologic variety of linear verrucous nevus that clinically appears inflammatory and histopathologically appears psoriasiform. The etiology of ILVEN remains unknown. It is considered a variant of keratinocytic epidermal nevus. Most cases are sporadic, but a familial case, with the condition occurring in a mother and her daughter, has been described.3 Because ILVEN bears some histologic resemblance to psoriasis, some authors believe that the 2 conditions share a common pathogenesis, possibly mediated by cytokines.4 There is some evidence that interleukins 1 and 6, tumor necrosis factor α, and intercellular adhesion molecule-1 are upregulated in ILVEN, similar to psoriasis.4 It also has been proposed that activation of an autosomal-dominant lethal mutation that survives by mosaicism may be the cause. The mutated cells might survive in the vicinity of the normal cells.5 ILVEN usually appears in infancy or early childhood but may be present at birth; the condition is very rarely present in adulthood.6 ILVEN occurs predominantly in females (female-male ratio, 4:1), and no racial predominance has been noted. About 6% of patients with epidermal nevi had ILVEN.6 ILVEN typically presents with multiple, discrete, erythematous, slightly warty and scaly papules that tend to coalesce into linear plaques. In a retrospective study of 23 patients with ILVEN, Lee and Rogers7 documented a predilection for the buttock and legs, and most cases were unilateral. Onset usually was within the first 6 months of life, most patients (16 patients) were male, and extension beyond the original margins occurred in 6 patients (26%).7 Altman and Mehregan² described 6 characteristic features of ILVEN: (1) early age of onset, (2) predominance in females (4:1 female-male ratio), (3) frequent involvement of the left leg, (4) pruritus, (5) marked refractoriness to therapy, and (6) a distinctive psoriasiform and inflammatory histologic appearance. In a few children, ILVEN has been found to occur in association with musculoskeletal or other abnormalities, including supernumerary digits and strabismus,8 congenital bony anomalies of the ipsilateral extremities,9 congenital dislocation of the ipsilateral hip and Fallot tetralogy of the heart,10 autoimmune thyroiditis,11 lichen amyloidosis,12 nevus depigmentosus,13 arthritis14 and melanodontia.15 More recently, ILVEN was associated with ipsilateral undescended testicle.16 However, this finding was disputed by Happle,17 who interpreted the case as an epidermal nevus of the epidermolytic type and stated that the ipsilateral cryptorchidism should be considered as a coincidental finding. The histopathologic presentation of ILVEN is very similar to psoriasis. Results of a histologic examination reveal psoriasiform hyperplasia of the epidermis, alternating parakeratosis without a granular layer, and orthokeratosis with a thickened granular layer.18 The authors of a recent study19 looked at advanced immunohistochemical methods to differentiate ILVEN from psoriasis. The investigators found that the number of Ki-67—positive nuclei tends to be lower, and the number of keratin-10—positive cells and HLA-DR expression tend to be higher in patients with ILVEN. The density of CD8+, CD45RO+, CD2+, CD94, and CD161 also showed a marked difference between ILVEN and psoriasis. In addition, the number of T cells relevant in the pathogenesis of psoriasis was markedly reduced in ILVEN.19 Other dermatoses that need to be differentiated from ILVEN are summarized in the Table. Nevoid psoriasis in a Blaschko distribution closely mimics ILVEN, but the former usually is asymptomatic and responds well to antipsoriatic treatment. Psoriasis also may become superimposed on an epidermal nevus because of Köbnerization.20

Epidermal nevi may occur almost anywhere on the head, neck, legs, or trunk.6 Nevus verrucosus is a term for the localized lesions of epidermal nevi.21 Linear verrucous epidermal nevi are linear hamartomas of epidermal structures that usually appear at birth or during infancy. Linear verrucous epidermal nevi usually are found on the lower extremities and have resistance to treatment and risk of recurrence. The nevi rarely are seen on the face and very rarely involve the oral mucosa.21 Clinically, there is no erythema or pruritus. Immunohistochemical studies further help differentiate ILVEN from other noninflammatory linear epidermal nevi. The CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) is characterized by segmentally distributed asymptomatic erythematous verrucous areas, associated with ipsilateral extremity defects, ranging from digital hypoplasia to agenesis of the extremity.22 Hence, ILVEN reported in association with severe extremity defects is most likely CHILD syndrome.23 An alternative acronym that has been used to describe this association is PENCIL (psoriasiform epidermal nevus with congenital ipsilateral limb defects).24 Lichen striatus usually is asymptomatic and resolves spontaneously. There also are histologic differences between ILVEN and lichen striatus.25 Linear lichen planus mainly affects children and is characterized by discrete pruritic, polygonal, violaceous papules arranged in a linear fashion, usually along an entire extremity; however, the papules also may be zosteriform.26 Linear porokeratosis also usually presents during childhood as ringlike, hypertrophic, verrucous plaques with a linear morphology, usually on a single extremity, but other parts of the body also may be involved.27 More recently, Jang et al28 reported a case of mycosis fungoides, presenting with a clinical picture of ILVEN. Nevoid basal cell carcinoma (BCC) syndrome is characterized by BCCs in both sun-exposed and nonexposed skin. The diameter of the lesions varies from 1 to 10 mm and commonly involves the face, back, and chest. Features such as odontogenic cysts, palmar and plantar pitting, and facial milia may be associated. Basaloid follicular hamartoma, also known as linear unilateral basal cell nevus with comedones, may present as a unilateral linear lesion.29 In its early stages, the lesion shows hypopigmented smooth or striaelike areas, which later may develop darker-pigmented papules and tumors with or without ulceration. Of note, it may be histologically indistinguishable from the infundibulocystic type of BCC.29 The most widely applied medical treatments for ILVEN have been intralesional corticosteroids or potent topical corticosteroids, the latter often with occlusion.30 However, the clinical appearance and associated intense pruritus usually are refractory to treatment. Topical calcipotriol has been reported to provide some relief in some patients,31 but it is not recommended in children because of limited clinical safety data. A recent case report noted improvement of pruritus in ILVEN with topical pimecrolimus cream.32 Dithranol has been used with success in one case report,33 but this has been interpreted as an antipsoriatic effect in ILVEN with superimposed psoriasis.34 Other therapeutic choices reported in the literature include topical tretinoin combined with 5-fluorouracil,35 and acitretin.36 Destructive therapies, such as the application of liquid nitrogen, electrodesiccation, ablative laser and dermabrasion, have all been equally disappointing.37 Of note, case reports have shown efficacy of CO238 and pulsed dye laser treatment.39 

Conclusion
ILVEN may be an isolated finding or may be associated with other abnormalities. Most patients pre-sent in infancy or early childhood. The diagnosis may sometimes be difficult and necessitate biopsy and advanced immunohistochemical analysis. Most lesions do not persist and spontaneously resolve by adulthood.40 The management usually is only symptomatic and often unsatisfactory.