Nonmelanoma Skin Cancer

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. 

Basaloid follicular hamartoma (BFH) is a benign adnexal tumor consisting of basaloid cells with follicular differentiation. BFH can occur as a solitary lesion, multiple lesions, or an autosomal dominant inherited syndrome—BFH syndrome (BFHS).1 In patients with BFHS, adnexal tumors predominantly occur on the head, neck, and torso. The syndrome often has coexisting hypotrichosis, hypohidrosis, and palmar/plantar pitting.1 A familial presentation of BFHS with palmar pitting is discussed with a review of BFHS, including the differential diagnosis of palmar pitting. 

Case Report
A 67-year-old white woman presented to dermatology with a 20-year history of several lesions on her face that started as flesh-colored papules and progressively darkened. Most lesions were 3 to 6 mm and located symmetrically around the nose, mouth, chin, and eyes. The woman presented with her 39-year-old daughter, who had a 2-year history of similar lesions around her eyes, none in a perioral distribution. The women reported that when the mother's lesions first appeared, they had the same appearance as the daughter's lesions. The persistent lesions were otherwise asymptomatic. Review of systems for both the mother and daughter were negative for other cutaneous lesions and for systemic symptoms such as fever; weight loss; and cardiovascular, respiratory, gastrointestinal, and genitourinary symptoms. The mother's medical history was significant for hypertension, diabetes mellitus, hypothyroidism, and hypercholesterolemia. The daughter's medical history was significant only for diabetes mellitus. Results of a physical examination of the mother revealed hundreds of soft flesh-colored to hyperpigmented papules, most less than 6 mm in diameter. The papules coalesced in the perioral distribution (Figure 1). Results of a physical examination of the daughter revealed similar symmetric distribution of small (most 1–2 mm but all <6 mm in diameter) flesh-colored papules in bilateral nasolabial and periorbital areas. Symmetric palmar pitting was present in both women (Figure 2). The patients had no other clinical manifestations such as frontoparietal bossing, high arched palates, jaw cysts, short fourth metacarpals, ocular hypertelorism, or narrow sloping shoulders to suggest nevoid basal cell carcinoma syndrome (NBCS). Histopathology results of both the mother and daughter revealed adnexal proliferation with follicular differentiation consistent with BFH (Figures 3–5).

Comment

BFH is a rare benign adnexal tumor that exhibits protean clinical manifestations. Despite the polymorphic clinical presentations, lesions exhibit similar histologic appearance, with only small variations.1,2 Lesions exist in both solitary and multiple forms.1-4 Multiple forms generally exhibit autosomal dominant inheritance, while solitary forms usually are not inherited.3 The solitary noninherited forms are more common than the multiple autosomal dominant inherited forms.3,5

Most reported solitary cases of BFH are in women, aged 20 to 88 years (median, 66 years; mean, 63 years).3 Patients with multiple familial disease may exhibit associated systemic diseases, though systemic disease is less likely in patients with solitary lesions.2,3 Systemic diseases that may be associated with BFHS include hypertension, cardiovascular disease, renal disease, obesity, carpal tunnel syndrome, and cancer of the breast and stomach.6 Generalized lesions also have been associated with cystic fibrosis,7 systemic lupus erythematosus,8 and myasthenia gravis.9

BFHS lesions have a predilection for the face and scalp but also have been reported on the neck, axillae, shoulders, and pubic regions.4 Wheeler et al6 examined 18 members in one family and found that dominantly-inherited generalized BFHS exhibits variability of disease. The patients exhibited lesions that ranged from hundreds of pigmented papules with associated hypotrichosis and palmar/ plantar pitting to minimal facial papules and a few milia involving only the face.6 Most papules are 1 to 2 mm.3 In mild forms, the lesions may go unnoticed or may be mistaken as normal.6 Lesions also may be present at birth or may develop in early childhood.6,10-12

Findings on physical examination most commonly associated with BFHS include milialike papules, comedonal-like papules, hypotrichosis, hypohidrosis, and palmar/plantar pitting (Table).6 Less common associated findings include atopic dermatitis, keratosis pilaris, lichen striatus, acrochordons, acanthosis nigricans—like changes, dermatosis papulosa nigra, acne vulgaris, café au lait spots, punctate palmar keratosis, and steatocystoma multiplex.6

The differential diagnoses of multiple facial papules include angiofibromas (tuberous sclerosis), multiple trichilemmomas (Cowden disease), multiple trichoepitheliomas, multiple syringomas, steatocystoma multiplex, seborrheic keratosis, melanocytic nevi, sebaceous hyperplasia, and NBCS or Gorlin syndrome.3 NBCS is believed to be caused by a lack of human homoloque patched (PTCH) tumor suppressor gene function, whereas BFHS is reported to be caused by a decrease in PTCH function.13 Girardi et al10 suggested that familial BFHS possibly is a forme fruste of NBCS (ie, since both entities involve the PTCH gene protein product or some member of its pathway).

Histologically, branching cords and thin strands of undifferentiated and anastomosing basaloid proliferations, which are surrounded by a loosely fibroblastic stroma, identify BFH.1 This histologic pattern may be found in a wide spectrum of clinically nevoid presentations, and individual lesions may be indistinguishable from infundibulocystic basal cell carcinoma (BCC). Occasional peripheral pallisading, papillary mesenchymal bodies, and connections to the epidermis also have been described.1

BFH is categorized within the spectrum of basaloid epithelial neoplasms associated with dysregulation of the PTCH signaling pathway.13 However, in general, BFH lesions show less mitotic figures and necrosis when compared with BCC.6,13 Immunohistochemistry results show CD34+ stromal cells in peritumoral distribution, resembling trichoepithelioma and distinguishing the condition from BCC, which lacks CD34 expression.14 Additional factors that distinguish BFH from BCC include BFH’s low proliferative index (ie, low Ki-67) and lack of bcl-2 expression.13,14

BFHS is a rare entity. It is a mainly histologic diagnosis with varied clinical presentations.6 Prognosis is good and treatment usually is cosmetic with shave, curette, or scissor methods most frequently reported.3 Because of the benign nature of this follicular tumor, observation without treatment is an option. It is important to be able to recognize this disease to avoid overaggressive surgical management and to closely monitor for any new tumors that may develop in these lesions.1 Monitoring and close follow-up of these lesions is necessary because some believe that familial BFHS is possibly a forme fruste of NBCS. Any indications of malignant changes in these lesions (eg, nonhealing and bleeding lesions, biopsy suggestive of BCC or other skin cancer) warrant surgical therapy. If lesions do not indicate malignant change, however, they may be removed for cosmetic reasons, but aggressive surgery, such as Mohs micrographic surgery, may put the patient at risk for unnecessary infection and increased morbidity.1

Basaloid follicular hamartoma (BFH) is a benign adnexal tumor consisting of basaloid cells with follicular differentiation. BFH can occur as a solitary lesion, multiple lesions, or an autosomal dominant inherited syndrome—BFH syndrome (BFHS).1 In patients with BFHS, adnexal tumors predominantly occur on the head, neck, and torso. The syndrome often has coexisting hypotrichosis, hypohidrosis, and palmar/plantar pitting.1 A familial presentation of BFHS with palmar pitting is discussed with a review of BFHS, including the differential diagnosis of palmar pitting. 

Case Report
A 67-year-old white woman presented to dermatology with a 20-year history of several lesions on her face that started as flesh-colored papules and progressively darkened. Most lesions were 3 to 6 mm and located symmetrically around the nose, mouth, chin, and eyes. The woman presented with her 39-year-old daughter, who had a 2-year history of similar lesions around her eyes, none in a perioral distribution. The women reported that when the mother's lesions first appeared, they had the same appearance as the daughter's lesions. The persistent lesions were otherwise asymptomatic. Review of systems for both the mother and daughter were negative for other cutaneous lesions and for systemic symptoms such as fever; weight loss; and cardiovascular, respiratory, gastrointestinal, and genitourinary symptoms. The mother's medical history was significant for hypertension, diabetes mellitus, hypothyroidism, and hypercholesterolemia. The daughter's medical history was significant only for diabetes mellitus. Results of a physical examination of the mother revealed hundreds of soft flesh-colored to hyperpigmented papules, most less than 6 mm in diameter. The papules coalesced in the perioral distribution (Figure 1). Results of a physical examination of the daughter revealed similar symmetric distribution of small (most 1–2 mm but all <6 mm in diameter) flesh-colored papules in bilateral nasolabial and periorbital areas. Symmetric palmar pitting was present in both women (Figure 2). The patients had no other clinical manifestations such as frontoparietal bossing, high arched palates, jaw cysts, short fourth metacarpals, ocular hypertelorism, or narrow sloping shoulders to suggest nevoid basal cell carcinoma syndrome (NBCS). Histopathology results of both the mother and daughter revealed adnexal proliferation with follicular differentiation consistent with BFH (Figures 3–5).

Comment

BFH is a rare benign adnexal tumor that exhibits protean clinical manifestations. Despite the polymorphic clinical presentations, lesions exhibit similar histologic appearance, with only small variations.1,2 Lesions exist in both solitary and multiple forms.1-4 Multiple forms generally exhibit autosomal dominant inheritance, while solitary forms usually are not inherited.3 The solitary noninherited forms are more common than the multiple autosomal dominant inherited forms.3,5

Most reported solitary cases of BFH are in women, aged 20 to 88 years (median, 66 years; mean, 63 years).3 Patients with multiple familial disease may exhibit associated systemic diseases, though systemic disease is less likely in patients with solitary lesions.2,3 Systemic diseases that may be associated with BFHS include hypertension, cardiovascular disease, renal disease, obesity, carpal tunnel syndrome, and cancer of the breast and stomach.6 Generalized lesions also have been associated with cystic fibrosis,7 systemic lupus erythematosus,8 and myasthenia gravis.9

BFHS lesions have a predilection for the face and scalp but also have been reported on the neck, axillae, shoulders, and pubic regions.4 Wheeler et al6 examined 18 members in one family and found that dominantly-inherited generalized BFHS exhibits variability of disease. The patients exhibited lesions that ranged from hundreds of pigmented papules with associated hypotrichosis and palmar/ plantar pitting to minimal facial papules and a few milia involving only the face.6 Most papules are 1 to 2 mm.3 In mild forms, the lesions may go unnoticed or may be mistaken as normal.6 Lesions also may be present at birth or may develop in early childhood.6,10-12

Findings on physical examination most commonly associated with BFHS include milialike papules, comedonal-like papules, hypotrichosis, hypohidrosis, and palmar/plantar pitting (Table).6 Less common associated findings include atopic dermatitis, keratosis pilaris, lichen striatus, acrochordons, acanthosis nigricans—like changes, dermatosis papulosa nigra, acne vulgaris, café au lait spots, punctate palmar keratosis, and steatocystoma multiplex.6

The differential diagnoses of multiple facial papules include angiofibromas (tuberous sclerosis), multiple trichilemmomas (Cowden disease), multiple trichoepitheliomas, multiple syringomas, steatocystoma multiplex, seborrheic keratosis, melanocytic nevi, sebaceous hyperplasia, and NBCS or Gorlin syndrome.3 NBCS is believed to be caused by a lack of human homoloque patched (PTCH) tumor suppressor gene function, whereas BFHS is reported to be caused by a decrease in PTCH function.13 Girardi et al10 suggested that familial BFHS possibly is a forme fruste of NBCS (ie, since both entities involve the PTCH gene protein product or some member of its pathway).

Histologically, branching cords and thin strands of undifferentiated and anastomosing basaloid proliferations, which are surrounded by a loosely fibroblastic stroma, identify BFH.1 This histologic pattern may be found in a wide spectrum of clinically nevoid presentations, and individual lesions may be indistinguishable from infundibulocystic basal cell carcinoma (BCC). Occasional peripheral pallisading, papillary mesenchymal bodies, and connections to the epidermis also have been described.1

BFH is categorized within the spectrum of basaloid epithelial neoplasms associated with dysregulation of the PTCH signaling pathway.13 However, in general, BFH lesions show less mitotic figures and necrosis when compared with BCC.6,13 Immunohistochemistry results show CD34+ stromal cells in peritumoral distribution, resembling trichoepithelioma and distinguishing the condition from BCC, which lacks CD34 expression.14 Additional factors that distinguish BFH from BCC include BFH’s low proliferative index (ie, low Ki-67) and lack of bcl-2 expression.13,14

BFHS is a rare entity. It is a mainly histologic diagnosis with varied clinical presentations.6 Prognosis is good and treatment usually is cosmetic with shave, curette, or scissor methods most frequently reported.3 Because of the benign nature of this follicular tumor, observation without treatment is an option. It is important to be able to recognize this disease to avoid overaggressive surgical management and to closely monitor for any new tumors that may develop in these lesions.1 Monitoring and close follow-up of these lesions is necessary because some believe that familial BFHS is possibly a forme fruste of NBCS. Any indications of malignant changes in these lesions (eg, nonhealing and bleeding lesions, biopsy suggestive of BCC or other skin cancer) warrant surgical therapy. If lesions do not indicate malignant change, however, they may be removed for cosmetic reasons, but aggressive surgery, such as Mohs micrographic surgery, may put the patient at risk for unnecessary infection and increased morbidity.1

Basaloid follicular hamartoma (BFH) is a benign adnexal tumor consisting of basaloid cells with follicular differentiation. BFH can occur as a solitary lesion, multiple lesions, or an autosomal dominant inherited syndrome—BFH syndrome (BFHS).1 In patients with BFHS, adnexal tumors predominantly occur on the head, neck, and torso. The syndrome often has coexisting hypotrichosis, hypohidrosis, and palmar/plantar pitting.1 A familial presentation of BFHS with palmar pitting is discussed with a review of BFHS, including the differential diagnosis of palmar pitting. 

Case Report
A 67-year-old white woman presented to dermatology with a 20-year history of several lesions on her face that started as flesh-colored papules and progressively darkened. Most lesions were 3 to 6 mm and located symmetrically around the nose, mouth, chin, and eyes. The woman presented with her 39-year-old daughter, who had a 2-year history of similar lesions around her eyes, none in a perioral distribution. The women reported that when the mother's lesions first appeared, they had the same appearance as the daughter's lesions. The persistent lesions were otherwise asymptomatic. Review of systems for both the mother and daughter were negative for other cutaneous lesions and for systemic symptoms such as fever; weight loss; and cardiovascular, respiratory, gastrointestinal, and genitourinary symptoms. The mother's medical history was significant for hypertension, diabetes mellitus, hypothyroidism, and hypercholesterolemia. The daughter's medical history was significant only for diabetes mellitus. Results of a physical examination of the mother revealed hundreds of soft flesh-colored to hyperpigmented papules, most less than 6 mm in diameter. The papules coalesced in the perioral distribution (Figure 1). Results of a physical examination of the daughter revealed similar symmetric distribution of small (most 1–2 mm but all <6 mm in diameter) flesh-colored papules in bilateral nasolabial and periorbital areas. Symmetric palmar pitting was present in both women (Figure 2). The patients had no other clinical manifestations such as frontoparietal bossing, high arched palates, jaw cysts, short fourth metacarpals, ocular hypertelorism, or narrow sloping shoulders to suggest nevoid basal cell carcinoma syndrome (NBCS). Histopathology results of both the mother and daughter revealed adnexal proliferation with follicular differentiation consistent with BFH (Figures 3–5).

Comment

BFH is a rare benign adnexal tumor that exhibits protean clinical manifestations. Despite the polymorphic clinical presentations, lesions exhibit similar histologic appearance, with only small variations.1,2 Lesions exist in both solitary and multiple forms.1-4 Multiple forms generally exhibit autosomal dominant inheritance, while solitary forms usually are not inherited.3 The solitary noninherited forms are more common than the multiple autosomal dominant inherited forms.3,5

Most reported solitary cases of BFH are in women, aged 20 to 88 years (median, 66 years; mean, 63 years).3 Patients with multiple familial disease may exhibit associated systemic diseases, though systemic disease is less likely in patients with solitary lesions.2,3 Systemic diseases that may be associated with BFHS include hypertension, cardiovascular disease, renal disease, obesity, carpal tunnel syndrome, and cancer of the breast and stomach.6 Generalized lesions also have been associated with cystic fibrosis,7 systemic lupus erythematosus,8 and myasthenia gravis.9

BFHS lesions have a predilection for the face and scalp but also have been reported on the neck, axillae, shoulders, and pubic regions.4 Wheeler et al6 examined 18 members in one family and found that dominantly-inherited generalized BFHS exhibits variability of disease. The patients exhibited lesions that ranged from hundreds of pigmented papules with associated hypotrichosis and palmar/ plantar pitting to minimal facial papules and a few milia involving only the face.6 Most papules are 1 to 2 mm.3 In mild forms, the lesions may go unnoticed or may be mistaken as normal.6 Lesions also may be present at birth or may develop in early childhood.6,10-12

Findings on physical examination most commonly associated with BFHS include milialike papules, comedonal-like papules, hypotrichosis, hypohidrosis, and palmar/plantar pitting (Table).6 Less common associated findings include atopic dermatitis, keratosis pilaris, lichen striatus, acrochordons, acanthosis nigricans—like changes, dermatosis papulosa nigra, acne vulgaris, café au lait spots, punctate palmar keratosis, and steatocystoma multiplex.6

The differential diagnoses of multiple facial papules include angiofibromas (tuberous sclerosis), multiple trichilemmomas (Cowden disease), multiple trichoepitheliomas, multiple syringomas, steatocystoma multiplex, seborrheic keratosis, melanocytic nevi, sebaceous hyperplasia, and NBCS or Gorlin syndrome.3 NBCS is believed to be caused by a lack of human homoloque patched (PTCH) tumor suppressor gene function, whereas BFHS is reported to be caused by a decrease in PTCH function.13 Girardi et al10 suggested that familial BFHS possibly is a forme fruste of NBCS (ie, since both entities involve the PTCH gene protein product or some member of its pathway).

Histologically, branching cords and thin strands of undifferentiated and anastomosing basaloid proliferations, which are surrounded by a loosely fibroblastic stroma, identify BFH.1 This histologic pattern may be found in a wide spectrum of clinically nevoid presentations, and individual lesions may be indistinguishable from infundibulocystic basal cell carcinoma (BCC). Occasional peripheral pallisading, papillary mesenchymal bodies, and connections to the epidermis also have been described.1

BFH is categorized within the spectrum of basaloid epithelial neoplasms associated with dysregulation of the PTCH signaling pathway.13 However, in general, BFH lesions show less mitotic figures and necrosis when compared with BCC.6,13 Immunohistochemistry results show CD34+ stromal cells in peritumoral distribution, resembling trichoepithelioma and distinguishing the condition from BCC, which lacks CD34 expression.14 Additional factors that distinguish BFH from BCC include BFH’s low proliferative index (ie, low Ki-67) and lack of bcl-2 expression.13,14

BFHS is a rare entity. It is a mainly histologic diagnosis with varied clinical presentations.6 Prognosis is good and treatment usually is cosmetic with shave, curette, or scissor methods most frequently reported.3 Because of the benign nature of this follicular tumor, observation without treatment is an option. It is important to be able to recognize this disease to avoid overaggressive surgical management and to closely monitor for any new tumors that may develop in these lesions.1 Monitoring and close follow-up of these lesions is necessary because some believe that familial BFHS is possibly a forme fruste of NBCS. Any indications of malignant changes in these lesions (eg, nonhealing and bleeding lesions, biopsy suggestive of BCC or other skin cancer) warrant surgical therapy. If lesions do not indicate malignant change, however, they may be removed for cosmetic reasons, but aggressive surgery, such as Mohs micrographic surgery, may put the patient at risk for unnecessary infection and increased morbidity.1