Laura A. Gonzalez-Krellwitz, MD

The Diagnosis: Microcystic Lymphatic Malformation

A punch biopsy demonstrated anastomosing fluidfilled spaces within the papillary and reticular dermal layers (Figure), confirming the diagnosis of microcystic lymphatic malformation (LM)(formerly known as lymphangioma circumscriptum), a congenital vascular malformation composed of slow-flow lymphatic channels.1 The patient underwent serial excisions with improvement of the LM, though the treatment course was complicated by hypertrophic scar formation.

The classic clinical presentation of microcystic LM includes a crop of vesicles containing clear or hemorrhagic fluid with associated oozing or bleeding.² When cutaneous lesions resembling microcystic LM develop in response to lymphatic damage and resulting stasis, such as from prior radiotherapy or surgery, the term lymphangiectasia is used to distinguish this entity from congenital microcystic LM.³

Microcystic LMs are histologically indistinguishable from macrocystic LMs; however, macrocystic LMs typically are clinically evident at birth as ill-defined subcutaneous masses.^2,4-6 Dermatitis herpetiformis, a dermatologic manifestation of gluten sensitivity, causes intensely pruritic vesicles in a symmetric distribution on the elbows, knees, and buttocks. Histopathology shows neutrophilic microabscesses in the dermal papillae with subepidermal blistering. Direct immunofluorescence demonstrates the deposition of IgA along the basement membrane with dermal papillae aggregates.⁶ The underlying dermis also may contain a lymphohistiocytic infiltrate rich in neutrophils. The vesicles of herpes zoster virus are painful and present in a dermatomal distribution. A viral cytopathic effect often is observed in keratinocytes, specifically with multinucleation, molding, and margination of chromatin material. The lesions are accompanied by variable lymphocytic inflammation and epithelial necrosis resulting in intraepidermal blistering.⁷ Extragenital lichen sclerosus presents as polygonal white papules merging to form plaques and may include hemorrhagic blisters in some instances. Histopathology shows hyperkeratosis, epidermal atrophy with flattened rete ridges, vacuolar interface changes, loss of elastic fibers, and hyalinization of the lamina propria with lymphocytic infiltrate.⁸

Endothelial cells in LM exhibit activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene, PIK3CA, which may lead to proliferation and overgrowth of the lymphatic vasculature, as well as increased production of cyclic guanosine monophosphate.^9,10 Phosphodiesterase 5 (PDE5) is expressed in the perivascular smooth muscle adjacent to lymphatic spaces in LMs but not in the their vasculature. 10 This pattern of PDE5 expression may cause perilesional vasculature to constrict, preventing lymphatic fluid from draining into the veins.¹¹ It is theorized that the PDE5 inhibitor sildenafil leads to relaxation of the vasculature adjacent to LMs, allowing the outflow of the accumulated lymphatic fluid and thus decompression.^11-13

Management of LM should not only take into account the depth and location of involvement but also any associated symptoms or complications, such as pruritus, pain, bleeding, or secondary infections. Magnetic resonance imaging (MRI) typically has been considered the gold standard for determining the size and depth of involvement of the malformation.^1,3,4 However, ultrasonography with Doppler flow may be considered an initial diagnostic and screening test, as it can distinguish between macrocystic and microcystic components and provide superior images of microcystic lesions, which are below the resolution capacity of MRI.4 Notably, our patient’s LM was undetectable on ultrasonography and was found to be largely superficial in nature on MRI.

Serial excision of the microcystic LM was conducted in our patient, but there currently is no consensus on optimal treatment of LM, and many treatment options are complicated by high recurrence rates or complications.⁵ Procedural approaches may include excision, cryotherapy, radiotherapy, sclerotherapy, or laser therapy, while pharmacologic approaches may include sildenafil for its inhibition of PDE5 or sirolimus (oral or topical) for its inhibition of mammalian target of rapamycin.^5,12-14 Because recurrence is highly likely, patients may require repeat treatments or a combination approach to therapy.^1,5 The development of targeted therapies may lead to a shift in management of LMs in the future, as successful use of the PIK3CA inhibitor alpelisib recently has been reported to lead to clinical improvement of PIK3CA-related LMs, including in patients with PIK3CA-related overgrowth syndromes.¹⁵

The Diagnosis: Microcystic Lymphatic Malformation

A punch biopsy demonstrated anastomosing fluidfilled spaces within the papillary and reticular dermal layers (Figure), confirming the diagnosis of microcystic lymphatic malformation (LM)(formerly known as lymphangioma circumscriptum), a congenital vascular malformation composed of slow-flow lymphatic channels.1 The patient underwent serial excisions with improvement of the LM, though the treatment course was complicated by hypertrophic scar formation.

The classic clinical presentation of microcystic LM includes a crop of vesicles containing clear or hemorrhagic fluid with associated oozing or bleeding.² When cutaneous lesions resembling microcystic LM develop in response to lymphatic damage and resulting stasis, such as from prior radiotherapy or surgery, the term lymphangiectasia is used to distinguish this entity from congenital microcystic LM.³

Microcystic LMs are histologically indistinguishable from macrocystic LMs; however, macrocystic LMs typically are clinically evident at birth as ill-defined subcutaneous masses.^2,4-6 Dermatitis herpetiformis, a dermatologic manifestation of gluten sensitivity, causes intensely pruritic vesicles in a symmetric distribution on the elbows, knees, and buttocks. Histopathology shows neutrophilic microabscesses in the dermal papillae with subepidermal blistering. Direct immunofluorescence demonstrates the deposition of IgA along the basement membrane with dermal papillae aggregates.⁶ The underlying dermis also may contain a lymphohistiocytic infiltrate rich in neutrophils. The vesicles of herpes zoster virus are painful and present in a dermatomal distribution. A viral cytopathic effect often is observed in keratinocytes, specifically with multinucleation, molding, and margination of chromatin material. The lesions are accompanied by variable lymphocytic inflammation and epithelial necrosis resulting in intraepidermal blistering.⁷ Extragenital lichen sclerosus presents as polygonal white papules merging to form plaques and may include hemorrhagic blisters in some instances. Histopathology shows hyperkeratosis, epidermal atrophy with flattened rete ridges, vacuolar interface changes, loss of elastic fibers, and hyalinization of the lamina propria with lymphocytic infiltrate.⁸

Endothelial cells in LM exhibit activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene, PIK3CA, which may lead to proliferation and overgrowth of the lymphatic vasculature, as well as increased production of cyclic guanosine monophosphate.^9,10 Phosphodiesterase 5 (PDE5) is expressed in the perivascular smooth muscle adjacent to lymphatic spaces in LMs but not in the their vasculature. 10 This pattern of PDE5 expression may cause perilesional vasculature to constrict, preventing lymphatic fluid from draining into the veins.¹¹ It is theorized that the PDE5 inhibitor sildenafil leads to relaxation of the vasculature adjacent to LMs, allowing the outflow of the accumulated lymphatic fluid and thus decompression.^11-13

Management of LM should not only take into account the depth and location of involvement but also any associated symptoms or complications, such as pruritus, pain, bleeding, or secondary infections. Magnetic resonance imaging (MRI) typically has been considered the gold standard for determining the size and depth of involvement of the malformation.^1,3,4 However, ultrasonography with Doppler flow may be considered an initial diagnostic and screening test, as it can distinguish between macrocystic and microcystic components and provide superior images of microcystic lesions, which are below the resolution capacity of MRI.4 Notably, our patient’s LM was undetectable on ultrasonography and was found to be largely superficial in nature on MRI.

Serial excision of the microcystic LM was conducted in our patient, but there currently is no consensus on optimal treatment of LM, and many treatment options are complicated by high recurrence rates or complications.⁵ Procedural approaches may include excision, cryotherapy, radiotherapy, sclerotherapy, or laser therapy, while pharmacologic approaches may include sildenafil for its inhibition of PDE5 or sirolimus (oral or topical) for its inhibition of mammalian target of rapamycin.^5,12-14 Because recurrence is highly likely, patients may require repeat treatments or a combination approach to therapy.^1,5 The development of targeted therapies may lead to a shift in management of LMs in the future, as successful use of the PIK3CA inhibitor alpelisib recently has been reported to lead to clinical improvement of PIK3CA-related LMs, including in patients with PIK3CA-related overgrowth syndromes.¹⁵

The Diagnosis: Microcystic Lymphatic Malformation

A punch biopsy demonstrated anastomosing fluidfilled spaces within the papillary and reticular dermal layers (Figure), confirming the diagnosis of microcystic lymphatic malformation (LM)(formerly known as lymphangioma circumscriptum), a congenital vascular malformation composed of slow-flow lymphatic channels.1 The patient underwent serial excisions with improvement of the LM, though the treatment course was complicated by hypertrophic scar formation.

The classic clinical presentation of microcystic LM includes a crop of vesicles containing clear or hemorrhagic fluid with associated oozing or bleeding.² When cutaneous lesions resembling microcystic LM develop in response to lymphatic damage and resulting stasis, such as from prior radiotherapy or surgery, the term lymphangiectasia is used to distinguish this entity from congenital microcystic LM.³

Microcystic LMs are histologically indistinguishable from macrocystic LMs; however, macrocystic LMs typically are clinically evident at birth as ill-defined subcutaneous masses.^2,4-6 Dermatitis herpetiformis, a dermatologic manifestation of gluten sensitivity, causes intensely pruritic vesicles in a symmetric distribution on the elbows, knees, and buttocks. Histopathology shows neutrophilic microabscesses in the dermal papillae with subepidermal blistering. Direct immunofluorescence demonstrates the deposition of IgA along the basement membrane with dermal papillae aggregates.⁶ The underlying dermis also may contain a lymphohistiocytic infiltrate rich in neutrophils. The vesicles of herpes zoster virus are painful and present in a dermatomal distribution. A viral cytopathic effect often is observed in keratinocytes, specifically with multinucleation, molding, and margination of chromatin material. The lesions are accompanied by variable lymphocytic inflammation and epithelial necrosis resulting in intraepidermal blistering.⁷ Extragenital lichen sclerosus presents as polygonal white papules merging to form plaques and may include hemorrhagic blisters in some instances. Histopathology shows hyperkeratosis, epidermal atrophy with flattened rete ridges, vacuolar interface changes, loss of elastic fibers, and hyalinization of the lamina propria with lymphocytic infiltrate.⁸

Endothelial cells in LM exhibit activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene, PIK3CA, which may lead to proliferation and overgrowth of the lymphatic vasculature, as well as increased production of cyclic guanosine monophosphate.^9,10 Phosphodiesterase 5 (PDE5) is expressed in the perivascular smooth muscle adjacent to lymphatic spaces in LMs but not in the their vasculature. 10 This pattern of PDE5 expression may cause perilesional vasculature to constrict, preventing lymphatic fluid from draining into the veins.¹¹ It is theorized that the PDE5 inhibitor sildenafil leads to relaxation of the vasculature adjacent to LMs, allowing the outflow of the accumulated lymphatic fluid and thus decompression.^11-13

Management of LM should not only take into account the depth and location of involvement but also any associated symptoms or complications, such as pruritus, pain, bleeding, or secondary infections. Magnetic resonance imaging (MRI) typically has been considered the gold standard for determining the size and depth of involvement of the malformation.^1,3,4 However, ultrasonography with Doppler flow may be considered an initial diagnostic and screening test, as it can distinguish between macrocystic and microcystic components and provide superior images of microcystic lesions, which are below the resolution capacity of MRI.4 Notably, our patient’s LM was undetectable on ultrasonography and was found to be largely superficial in nature on MRI.

Serial excision of the microcystic LM was conducted in our patient, but there currently is no consensus on optimal treatment of LM, and many treatment options are complicated by high recurrence rates or complications.⁵ Procedural approaches may include excision, cryotherapy, radiotherapy, sclerotherapy, or laser therapy, while pharmacologic approaches may include sildenafil for its inhibition of PDE5 or sirolimus (oral or topical) for its inhibition of mammalian target of rapamycin.^5,12-14 Because recurrence is highly likely, patients may require repeat treatments or a combination approach to therapy.^1,5 The development of targeted therapies may lead to a shift in management of LMs in the future, as successful use of the PIK3CA inhibitor alpelisib recently has been reported to lead to clinical improvement of PIK3CA-related LMs, including in patients with PIK3CA-related overgrowth syndromes.¹⁵

The Diagnosis: Juvenile Xanthogranuloma

Juvenile xanthogranuloma (JXG) was first described in 1905 by Adamson1 as solitary or multiple plaquiform or nodular lesions that are yellow to yellowish brown. In 1954, Helwig and Hackney² coined the term juvenile xanthogranuloma to define this histiocytic cutaneous granulomatous tumor.

Juvenile xanthogranuloma is a rare dermatologic disorder that may be present at birth and primarily affects infants and young children. The benign lesions generally occur in the first 4 years of life, with a median age of onset of 2 years.³ Lesions range in size from millimeters to several centimeters in diameter.⁴ The skin of the head and neck is the most commonly involved site in JXG. The most frequent noncutaneous site of JXG involvement is the eye, particularly the iris, accounting for 0.4% of cases.^5,6 Extracutaneous sites such as the heart, liver, lungs, spleen, oral cavity, and brain also may be involved.⁴

Most children with JXG are asymptomatic. Skin lesions present as well-demarcated, rubbery, tan-orange papules or nodules. They usually are solitary, and multiple nodules can increase the risk for extracutaneous involvement.⁴ A case series of patients with neurofibromatosis type 1 showed 14 of 77 (18%) patients examined in the first year of life presented with JXG or other non–Langerhans cell histiocytosis.⁷ The adult form of cutaneous xanthogranuloma often presents with severe bronchial asthma.⁸

Histopathologic examination of a biopsy of the lesion typically demonstrates well-circumscribed nodules with dense infiltrates of polyhedral histiocytes with vaculoles.^3-7 In 85% of cases, Touton giant cells are present.^4,9 A prominent vascular network often is present, which was observed in our patient’s biopsy (Figure 1). Immunohistochemistry typically is positive for CD14, CD68, CD163, fascin, and factor XIIIa.^4,10 Classically, the cells are negative for S-100 and CD1a, which differentiates these lesions from Langerhans cell histiocytosis.^4-7,10 Our patient demonstrated scattered S-100–positive cells representing background dendritic cells and macrophages (Figure 2). The remainder of the clinical, morphologic, and immunophenotypic findings were consistent with non–Langerhans cell histiocytosis, specifically JXG.

Biopsy should be performed in all cases, and basic laboratory test results such as a complete blood cell count and basic metabolic panel also are appropriate. Routine referral of all patients with cutaneous JXG for ophthalmologic evaluation is not recommended.¹¹ Most patients with ocular involvement present with acute ocular concerns; asymptomatic eye involvement is rare. It is reasonable to consider referral to ophthalmology for patients younger than 2 years who present with multiple lesions, as they may have a higher risk for ocular involvement.¹¹

Juvenile xanthogranuloma usually is a benign disorder with management involving observation, as the lesions typically involute spontaneously.^3-7,9,10,12 Systemic or intralesional corticosteroids may be used for treatment in lesions that do not resolve. Ocular JXG refractory to steroid treatment has been managed in several cases with intravitreal bevacizumab.¹³ Additionally, surgical excision can be considered if malignancy is suspected, the lesion does not resolve with observation or steroid treatment, or the lesion is located near vital structures.^4-7,9-13

Spitz nevus presents as a single dome-shaped papule, but histology shows a symmetrical proliferation of spindle and epithelioid cells. Trachoma can present in and around the eye as a follicular hypertrophy but most commonly is seen in the conjunctiva. Dermoid cysts present as solitary subcutaneous cystic lesions; histology demonstrates a lining of keratinizing squamous epithelium with the presence of pilosebaceous structures. Dermatofibroma appears as a tan to reddish-brown papule in an area of prior minor trauma; pathology demonstrates an acanthotic epidermis with an underlying zone of normal papillary dermis and unencapsulated lesions with spindle cells overlapping in fascicles and whorls at the periphery.

The Diagnosis: Juvenile Xanthogranuloma

Juvenile xanthogranuloma (JXG) was first described in 1905 by Adamson1 as solitary or multiple plaquiform or nodular lesions that are yellow to yellowish brown. In 1954, Helwig and Hackney² coined the term juvenile xanthogranuloma to define this histiocytic cutaneous granulomatous tumor.

Juvenile xanthogranuloma is a rare dermatologic disorder that may be present at birth and primarily affects infants and young children. The benign lesions generally occur in the first 4 years of life, with a median age of onset of 2 years.³ Lesions range in size from millimeters to several centimeters in diameter.⁴ The skin of the head and neck is the most commonly involved site in JXG. The most frequent noncutaneous site of JXG involvement is the eye, particularly the iris, accounting for 0.4% of cases.^5,6 Extracutaneous sites such as the heart, liver, lungs, spleen, oral cavity, and brain also may be involved.⁴

Most children with JXG are asymptomatic. Skin lesions present as well-demarcated, rubbery, tan-orange papules or nodules. They usually are solitary, and multiple nodules can increase the risk for extracutaneous involvement.⁴ A case series of patients with neurofibromatosis type 1 showed 14 of 77 (18%) patients examined in the first year of life presented with JXG or other non–Langerhans cell histiocytosis.⁷ The adult form of cutaneous xanthogranuloma often presents with severe bronchial asthma.⁸

Histopathologic examination of a biopsy of the lesion typically demonstrates well-circumscribed nodules with dense infiltrates of polyhedral histiocytes with vaculoles.^3-7 In 85% of cases, Touton giant cells are present.^4,9 A prominent vascular network often is present, which was observed in our patient’s biopsy (Figure 1). Immunohistochemistry typically is positive for CD14, CD68, CD163, fascin, and factor XIIIa.^4,10 Classically, the cells are negative for S-100 and CD1a, which differentiates these lesions from Langerhans cell histiocytosis.^4-7,10 Our patient demonstrated scattered S-100–positive cells representing background dendritic cells and macrophages (Figure 2). The remainder of the clinical, morphologic, and immunophenotypic findings were consistent with non–Langerhans cell histiocytosis, specifically JXG.

Biopsy should be performed in all cases, and basic laboratory test results such as a complete blood cell count and basic metabolic panel also are appropriate. Routine referral of all patients with cutaneous JXG for ophthalmologic evaluation is not recommended.¹¹ Most patients with ocular involvement present with acute ocular concerns; asymptomatic eye involvement is rare. It is reasonable to consider referral to ophthalmology for patients younger than 2 years who present with multiple lesions, as they may have a higher risk for ocular involvement.¹¹

Juvenile xanthogranuloma usually is a benign disorder with management involving observation, as the lesions typically involute spontaneously.^3-7,9,10,12 Systemic or intralesional corticosteroids may be used for treatment in lesions that do not resolve. Ocular JXG refractory to steroid treatment has been managed in several cases with intravitreal bevacizumab.¹³ Additionally, surgical excision can be considered if malignancy is suspected, the lesion does not resolve with observation or steroid treatment, or the lesion is located near vital structures.^4-7,9-13

Spitz nevus presents as a single dome-shaped papule, but histology shows a symmetrical proliferation of spindle and epithelioid cells. Trachoma can present in and around the eye as a follicular hypertrophy but most commonly is seen in the conjunctiva. Dermoid cysts present as solitary subcutaneous cystic lesions; histology demonstrates a lining of keratinizing squamous epithelium with the presence of pilosebaceous structures. Dermatofibroma appears as a tan to reddish-brown papule in an area of prior minor trauma; pathology demonstrates an acanthotic epidermis with an underlying zone of normal papillary dermis and unencapsulated lesions with spindle cells overlapping in fascicles and whorls at the periphery.

The Diagnosis: Juvenile Xanthogranuloma

Juvenile xanthogranuloma (JXG) was first described in 1905 by Adamson1 as solitary or multiple plaquiform or nodular lesions that are yellow to yellowish brown. In 1954, Helwig and Hackney² coined the term juvenile xanthogranuloma to define this histiocytic cutaneous granulomatous tumor.

Juvenile xanthogranuloma is a rare dermatologic disorder that may be present at birth and primarily affects infants and young children. The benign lesions generally occur in the first 4 years of life, with a median age of onset of 2 years.³ Lesions range in size from millimeters to several centimeters in diameter.⁴ The skin of the head and neck is the most commonly involved site in JXG. The most frequent noncutaneous site of JXG involvement is the eye, particularly the iris, accounting for 0.4% of cases.^5,6 Extracutaneous sites such as the heart, liver, lungs, spleen, oral cavity, and brain also may be involved.⁴

Most children with JXG are asymptomatic. Skin lesions present as well-demarcated, rubbery, tan-orange papules or nodules. They usually are solitary, and multiple nodules can increase the risk for extracutaneous involvement.⁴ A case series of patients with neurofibromatosis type 1 showed 14 of 77 (18%) patients examined in the first year of life presented with JXG or other non–Langerhans cell histiocytosis.⁷ The adult form of cutaneous xanthogranuloma often presents with severe bronchial asthma.⁸

Histopathologic examination of a biopsy of the lesion typically demonstrates well-circumscribed nodules with dense infiltrates of polyhedral histiocytes with vaculoles.^3-7 In 85% of cases, Touton giant cells are present.^4,9 A prominent vascular network often is present, which was observed in our patient’s biopsy (Figure 1). Immunohistochemistry typically is positive for CD14, CD68, CD163, fascin, and factor XIIIa.^4,10 Classically, the cells are negative for S-100 and CD1a, which differentiates these lesions from Langerhans cell histiocytosis.^4-7,10 Our patient demonstrated scattered S-100–positive cells representing background dendritic cells and macrophages (Figure 2). The remainder of the clinical, morphologic, and immunophenotypic findings were consistent with non–Langerhans cell histiocytosis, specifically JXG.

Biopsy should be performed in all cases, and basic laboratory test results such as a complete blood cell count and basic metabolic panel also are appropriate. Routine referral of all patients with cutaneous JXG for ophthalmologic evaluation is not recommended.¹¹ Most patients with ocular involvement present with acute ocular concerns; asymptomatic eye involvement is rare. It is reasonable to consider referral to ophthalmology for patients younger than 2 years who present with multiple lesions, as they may have a higher risk for ocular involvement.¹¹

Juvenile xanthogranuloma usually is a benign disorder with management involving observation, as the lesions typically involute spontaneously.^3-7,9,10,12 Systemic or intralesional corticosteroids may be used for treatment in lesions that do not resolve. Ocular JXG refractory to steroid treatment has been managed in several cases with intravitreal bevacizumab.¹³ Additionally, surgical excision can be considered if malignancy is suspected, the lesion does not resolve with observation or steroid treatment, or the lesion is located near vital structures.^4-7,9-13

Spitz nevus presents as a single dome-shaped papule, but histology shows a symmetrical proliferation of spindle and epithelioid cells. Trachoma can present in and around the eye as a follicular hypertrophy but most commonly is seen in the conjunctiva. Dermoid cysts present as solitary subcutaneous cystic lesions; histology demonstrates a lining of keratinizing squamous epithelium with the presence of pilosebaceous structures. Dermatofibroma appears as a tan to reddish-brown papule in an area of prior minor trauma; pathology demonstrates an acanthotic epidermis with an underlying zone of normal papillary dermis and unencapsulated lesions with spindle cells overlapping in fascicles and whorls at the periphery.