Nicole D. Boswell, MD

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Bullous Hemorrhagic Dermatosis

Biopsy results showed an intraepidermal blister with a floor composed of maturing epidermis. The roof of the blister was composed of necrotic keratinocytes with overlying orthokeratosis, and the cavity was filled with a moderate amount of fibrin and dead cells with neutrophils. Direct immunofluorescence (DIF) using specific antihuman IgG, IgM, IgA, C3, and fibrin was negative. Aerobic, anaerobic, and fungal cultures also were negative. With these histopathologic findings, medication exposure, and timing of bullae onset, our patient was diagnosed with bullous hemorrhagic dermatosis (BHD) secondary to enoxaparin administration. Enoxaparin was continued due to increased risk for coagulopathy, and there was complete resolution of the bullae after 5 weeks with no residual symptoms.

Bullous hemorrhagic dermatosis is a rare eruption that can occur after administration of heparin and low-molecular-weight heparin, with enoxaparin being the most commonly implicated drug.¹ The lesions typically are seen in elderly men in the seventh decade of life and appear within a median of 7 days after drug exposure. The time course for the postexposure eruption can vary from 2 to 21 days, with reports of skin lesions appearing up to 4 months after exposure.^1,2 hemorrhagic bullae (Figure) typically on the arms and legs, though lesions also can develop on the trunk. The lesions can occur in distant areas from the injection site, suggesting BHD may be a systemic reaction, although the etiology is poorly understood.¹

Another heparin reaction that can manifest similarly to BHD is heparin-induced skin necrosis.³ Patients with this condition also may have associated heparin-induced thrombocytopenia upon laboratory investigation and have a more aggressive clinical course than BHD. Biopsy can help differentiate BHD and early heparin-induced skin necrosis if the clinical manifestation is unclear. Histopathologically, BHD typically has intraepidermal bullae filled with blood, whereas heparin-induced skin necrosis has dermal thrombi.^1,4 Treatment of both conditions differs in whether to discontinue anticoagulants: heparin-induced skin necrosis requires discontinuation of the medication, while BHD does not.^2,3

In patients with BHD, the lesions are self-resolving, and treatment is supportive, although whether enoxaparin is discontinued varies among physicians.² Lesions typically resolve within 2 weeks of onset, although it is unclear whether continuing anticoagulants delays resolution.¹ Discontinuing anticoagulants in certain patients can be life-threatening due to complex comorbidities (eg, risk for venous thromboembolism or pulmonary embolism from prolonged hospitalization or severe trauma) and is not necessary for the resolution of BHD.

In addition to BHD and heparin-induced skin necrosis, our differential diagnosis included bullous pemphigoid, coma blisters, and Vibrio vulnificus infection. Although bullous pemphigoid can manifest with tense bullae that are pauci-inflammatory on histology, DIF would show linear IgG and C3 deposition at the dermal-epidermal junction. In our patient, DIF was negative and favored another etiology for the lesions. Coma blisters can occur in areas of sustained pressure and typically develop in patients with a prolonged hospitalization or those who are sedentary for long periods of time. The distribution of bullae on our patient’s bilateral pretibial shins made this diagnosis unlikely. Vibrio vulnificus infection can manifest as hemorrhagic bullae, though typically after a break in the skin exposed to brackish water. Vibrio vulnificus infection can be life-threatening, resulting in septicemia and increased mortality, and a thorough patient history is important for diagnosis.⁵

THE DIAGNOSIS: Bullous Hemorrhagic Dermatosis

Biopsy results showed an intraepidermal blister with a floor composed of maturing epidermis. The roof of the blister was composed of necrotic keratinocytes with overlying orthokeratosis, and the cavity was filled with a moderate amount of fibrin and dead cells with neutrophils. Direct immunofluorescence (DIF) using specific antihuman IgG, IgM, IgA, C3, and fibrin was negative. Aerobic, anaerobic, and fungal cultures also were negative. With these histopathologic findings, medication exposure, and timing of bullae onset, our patient was diagnosed with bullous hemorrhagic dermatosis (BHD) secondary to enoxaparin administration. Enoxaparin was continued due to increased risk for coagulopathy, and there was complete resolution of the bullae after 5 weeks with no residual symptoms.

Bullous hemorrhagic dermatosis is a rare eruption that can occur after administration of heparin and low-molecular-weight heparin, with enoxaparin being the most commonly implicated drug.¹ The lesions typically are seen in elderly men in the seventh decade of life and appear within a median of 7 days after drug exposure. The time course for the postexposure eruption can vary from 2 to 21 days, with reports of skin lesions appearing up to 4 months after exposure.^1,2 hemorrhagic bullae (Figure) typically on the arms and legs, though lesions also can develop on the trunk. The lesions can occur in distant areas from the injection site, suggesting BHD may be a systemic reaction, although the etiology is poorly understood.¹

Another heparin reaction that can manifest similarly to BHD is heparin-induced skin necrosis.³ Patients with this condition also may have associated heparin-induced thrombocytopenia upon laboratory investigation and have a more aggressive clinical course than BHD. Biopsy can help differentiate BHD and early heparin-induced skin necrosis if the clinical manifestation is unclear. Histopathologically, BHD typically has intraepidermal bullae filled with blood, whereas heparin-induced skin necrosis has dermal thrombi.^1,4 Treatment of both conditions differs in whether to discontinue anticoagulants: heparin-induced skin necrosis requires discontinuation of the medication, while BHD does not.^2,3

In patients with BHD, the lesions are self-resolving, and treatment is supportive, although whether enoxaparin is discontinued varies among physicians.² Lesions typically resolve within 2 weeks of onset, although it is unclear whether continuing anticoagulants delays resolution.¹ Discontinuing anticoagulants in certain patients can be life-threatening due to complex comorbidities (eg, risk for venous thromboembolism or pulmonary embolism from prolonged hospitalization or severe trauma) and is not necessary for the resolution of BHD.

In addition to BHD and heparin-induced skin necrosis, our differential diagnosis included bullous pemphigoid, coma blisters, and Vibrio vulnificus infection. Although bullous pemphigoid can manifest with tense bullae that are pauci-inflammatory on histology, DIF would show linear IgG and C3 deposition at the dermal-epidermal junction. In our patient, DIF was negative and favored another etiology for the lesions. Coma blisters can occur in areas of sustained pressure and typically develop in patients with a prolonged hospitalization or those who are sedentary for long periods of time. The distribution of bullae on our patient’s bilateral pretibial shins made this diagnosis unlikely. Vibrio vulnificus infection can manifest as hemorrhagic bullae, though typically after a break in the skin exposed to brackish water. Vibrio vulnificus infection can be life-threatening, resulting in septicemia and increased mortality, and a thorough patient history is important for diagnosis.⁵

THE DIAGNOSIS: Bullous Hemorrhagic Dermatosis

Biopsy results showed an intraepidermal blister with a floor composed of maturing epidermis. The roof of the blister was composed of necrotic keratinocytes with overlying orthokeratosis, and the cavity was filled with a moderate amount of fibrin and dead cells with neutrophils. Direct immunofluorescence (DIF) using specific antihuman IgG, IgM, IgA, C3, and fibrin was negative. Aerobic, anaerobic, and fungal cultures also were negative. With these histopathologic findings, medication exposure, and timing of bullae onset, our patient was diagnosed with bullous hemorrhagic dermatosis (BHD) secondary to enoxaparin administration. Enoxaparin was continued due to increased risk for coagulopathy, and there was complete resolution of the bullae after 5 weeks with no residual symptoms.

Bullous hemorrhagic dermatosis is a rare eruption that can occur after administration of heparin and low-molecular-weight heparin, with enoxaparin being the most commonly implicated drug.¹ The lesions typically are seen in elderly men in the seventh decade of life and appear within a median of 7 days after drug exposure. The time course for the postexposure eruption can vary from 2 to 21 days, with reports of skin lesions appearing up to 4 months after exposure.^1,2 hemorrhagic bullae (Figure) typically on the arms and legs, though lesions also can develop on the trunk. The lesions can occur in distant areas from the injection site, suggesting BHD may be a systemic reaction, although the etiology is poorly understood.¹

Another heparin reaction that can manifest similarly to BHD is heparin-induced skin necrosis.³ Patients with this condition also may have associated heparin-induced thrombocytopenia upon laboratory investigation and have a more aggressive clinical course than BHD. Biopsy can help differentiate BHD and early heparin-induced skin necrosis if the clinical manifestation is unclear. Histopathologically, BHD typically has intraepidermal bullae filled with blood, whereas heparin-induced skin necrosis has dermal thrombi.^1,4 Treatment of both conditions differs in whether to discontinue anticoagulants: heparin-induced skin necrosis requires discontinuation of the medication, while BHD does not.^2,3

In patients with BHD, the lesions are self-resolving, and treatment is supportive, although whether enoxaparin is discontinued varies among physicians.² Lesions typically resolve within 2 weeks of onset, although it is unclear whether continuing anticoagulants delays resolution.¹ Discontinuing anticoagulants in certain patients can be life-threatening due to complex comorbidities (eg, risk for venous thromboembolism or pulmonary embolism from prolonged hospitalization or severe trauma) and is not necessary for the resolution of BHD.

In addition to BHD and heparin-induced skin necrosis, our differential diagnosis included bullous pemphigoid, coma blisters, and Vibrio vulnificus infection. Although bullous pemphigoid can manifest with tense bullae that are pauci-inflammatory on histology, DIF would show linear IgG and C3 deposition at the dermal-epidermal junction. In our patient, DIF was negative and favored another etiology for the lesions. Coma blisters can occur in areas of sustained pressure and typically develop in patients with a prolonged hospitalization or those who are sedentary for long periods of time. The distribution of bullae on our patient’s bilateral pretibial shins made this diagnosis unlikely. Vibrio vulnificus infection can manifest as hemorrhagic bullae, though typically after a break in the skin exposed to brackish water. Vibrio vulnificus infection can be life-threatening, resulting in septicemia and increased mortality, and a thorough patient history is important for diagnosis.⁵