Dermatopathology

Case Report

A 49-year-old woman presented to the dermatology department with a concern of itching distributed along the V1 branch of the trigeminal nerve on the left frontoparietal scalp following a herpes zoster (HZ) outbreak in the same dermatome 2 months prior. She initially presented to the emergency department 2 months earlier with vesicular lesions distributed along the V1 branch of the trigeminal nerve, along with facial swelling, periorbital edema, inability to open the left eye, and “excruciating” pain. Her left eye was “itchy” but no ophthalmologic pathology was noted on examination. She was diagnosed with HZ and was treated with valacyclovir and prednisone. Oxycodone-acetaminophen followed by hydromorphone was prescribed for the severe pain with limited benefit. After completing treatment with valacyclovir, oral gabapentin was added for additional pain management, with an initial dose of 100 mg 3 times daily.

At the current presentation, the patient reported profound pruritus in the left frontoparietal scalp region that was intractable and debilitating. Some improvement of the itching was achieved with scratching that resulted in deep ulcerations of the scalp with moderate associated pain. In addition to the prior HZ outbreak, her medical history was remarkable for recurrent lymphoma, uterine cancer, chronic bronchitis, depression, hypothyroidism, osteoarthritis, and primary varicella-zoster virus infection in childhood. Her current medications included oral gabapentin (600 mg 3 times daily), diphenhydramine, levothyroxine, simvastatin, and topical ointments for itching.

On dermatologic evaluation, the patient rated her pain as a 5 on a 10-point scale of intensity. Alopecia involving the left frontoparietal scalp with a 2×3-cm ulceration in a geometric pattern with surrounding erythema was noted (Figure 1A). There also was hyperpigmentation on the forehead distributed along the V1 branch of the trigeminal nerve (Figure 1B). The patient also had been seen in the pain clinic where examination revealed sensory loss to both light touch and sharp stimulus along the left V1 branch of the trigeminal nerve. Visual fields were full, ocular movements were intact, and the face was symmetric with lower cranial nerves intact.

Figure 1. Alopecia involving the left frontoparietal scalp with a 2×3-cm ulceration in a geometric pattern with surrounding erythema (A). Hyperpigmentation distributed along the V1 branch of the trigeminal nerve due to postinflammatory changes following herpes zoster infection in the same dermatome (B).

A diagnosis of trigeminal trophic syndrome (TTS) with chronic pain and pruritus due to a complex sensory neural disorder associated with HZ reactivation was made. Treatment included an increase in the dosage of oral gabapentin (1200 mg 3 times daily), oral oxycodone (5 mg every 4 to 6 hours as needed), and sphenopalatine ganglion block on the left side in an attempt to decrease pain and pruritus. At 6-week follow-up, the patient had no improvement in symptoms.

Three scalp punch biopsies were performed on presentation to the dermatology clinic including 2 from the affected area on the left frontoparietal scalp, and one from normal skin on the right side to assess the small nerve fibers affected. Protein gene product 9.5 (PGP 9.5) immunostaining was performed to assess epidermal nerve fiber density. The left scalp biopsies were consistent with a complete focal sensory neuropathy affecting sensory and autonomic axons (Figure 2A). The right scalp biopsy revealed well-innervated skin (Figure 2B).

Figure 2. Fluorescent labeling with protein gene product 9.5 allowed for comparison of epidermal small nerve fibers on the affected (left) and unaffected (right) sides of the scalp. A biopsy of the left side of the scalp was consistent with a complete focal sensory neuropathy affecting sensory and autonomic axons, and complete absence of epidermal nerve fibers and subepidermal nerve plexus were seen (A)(original magnification ×20). On the right side of the scalp, well-innervated epidermal nerve fibers (white arrows) and subepidermal nerve plexus (green arrow) were seen (B)(original magnification ×20).

One year after the original HZ outbreak, the patient continued to have debilitating pruritus and pain in the affected dermatome. On physical examination at 1-year follow-up, the hyperpigmentation on the left side of the forehead showed minimal improvement. The ulcerations were healed, but excoriations were noted in the area. Having experienced some relief from titration of the dose of gabapentin 800 mg 3 times daily and doxepin 25 mg nightly at 1-year follow-up, the patient returned to work but remained highly distressed by her symptoms. Neurosurgery was consulted for possible balloon rhizotomy of the left trigeminal nerve, which she ultimately refused due to concerns about side effects.

Comment

Trophic trigeminal syndrome is characterized by unilateral ulceration of the face with anesthesia, paresthesia, and a crescent-shaped erosion or ulcer.^1,2 It is one of 2 causes of self-induced facial ulcerations, the other being factitial dermatitis.^1,3,4 A 2008 retrospective medical chart review and report of 14 cases helped elucidate the epidemiology of TTS.² In this case series, the female to male ratio was 6 to 1, and the mean age of TTS onset was 45 years (age range, 6–82 years). The cause of disease in most patients was iatrogenic and the latent period to onset ranged from days to almost one decade. Most patients self-manipulated the face (n=9), and most ulcers affected the second trigeminal division. Pain intensity was severe in most (n=6), and gabapentin offered relief in only 2 cases.²

The etiologies of TTS are wide ranging, and the differential diagnosis should be contemplated when patients present with facial ulcers. Most cases are iatrogenic secondary to trigeminal rhizotomy,⁵ alcohol injections into the gasserian ganglion, or electrocoagulation. Also common are cases caused by ischemic damage to the trigeminal ganglion⁶ or Wallenberg syndrome.⁷ More rare etiologies include trauma,⁷ craniotomy,⁷ astrocytoma, acoustic neuroma, meningioma,⁸ idiopathic causes, basal cell carcinoma, infectious diseases (eg, tertiary syphilis, recurrent herpes simplex virus, leishmaniasis, cutaneous tuberculosis, leprosy, HZ),^9-11 or systemic disease (eg, Wegener granulomatosis, Horton arteritis).

Trigeminal trophic syndrome is rare and there is little agreement on a treatment algorithm. As in our case, a methodical trial-and-error approach is suggested while encouraging the patient not to abandon treatment when efforts are not fruitful. The most important treatment strategy is behavioral modification; patients must become aware of the role of self-manipulation and assiduously avoid it. Using occlusive dressings at the affected site also may be helpful^3,12 Transcutaneous electrical nerve stimulation may lead to improvement, but relapse is common with treatment discontinuation. Therapies directed at reducing paresthesia (eg, carbamazepine, diazepam, amitriptyline, chlorpromazine, pimozide) are sometimes successful, but relapse is common.^1,3 Transplantation of in vitro–cultured epidermal cells is a new experimental treatment that offers hope for future success.¹³ Facial reconstruction of the affected area may help patients who can restrain themselves from self-manipulation.⁴

Skin biopsy findings in our case revealed an interesting aspect of the disease process of TTS. Skin biopsies are helpful in ruling out malignancy and specific stains can be used to further elucidate disease or pathologic processes occurring in the skin. In TTS, no specific changes are seen on hematoxylin and eosin staining, revealing only nonspecific inflammatory changes.^1,5 Strikingly, the pathology of affected skin in patients with postherpetic neuralgia often reveals distal nociceptive axon loss,⁹ as was seen in the skin biopsies from our patient’s left scalp. It has been proven by many researchers in many neuropathic pain conditions that the pathological signature of chronic neuropathic pain is reduction in the density of cutaneous nociceptive innervation.⁹ The most common method for visualizing cutaneous neuritis is using an immunohistochemical labeling method in which antibodies are directed against PGP 9.5. A pan-axonal neurofilament marker, PGP 9.5 allows for visualization of small sensory nerve endings in the skin. As nociceptive axons degenerate in neuropathic pain conditions, it is believed that initiation of proalgesic changes within remaining peripheral nerves and the central nervous system (CNS) occur. Another interesting aspect of our case was the patient’s persistent intractable itching and chronic pain 2 months following the initial HZ outbreak. Although pain and itching can be evoked by similar stimuli and injuries, it has been shown that both have separate neuronal pathways because they produce different conscious and reflex motor actions.¹⁴ For instance, pain causes a withdrawal reflex, while itching causes mechanical stimulation of the affected area. The act of itching is thought to have evolved to protect against threats by the act of dislodging the stimulus rather than withdrawing as seen in pain.¹⁴ It has been hypothesized that postherpetic itching (chronic pruritus following an HZ outbreak) is due to spontaneous firing of denervated CNS itch neurons.⁹

Postherpetic neuralgia–related pain seems to be most closely correlated with degeneration of varicella-zoster virus–infected primary afferent neurons. With deceased afferent neurons sending signals to the CNS and death or dysfunction of inhibitory interneurons in the dorsal horn of the spinal cord due to peripheral nerve injury, there is increased paradoxical electrical activity in specific CNS neurons. This CNS plasticity results in neuropathic pain and other altered sensory abnormalities in patients with TTS.⁹

Conclusion

We present a case of TTS distributed along the V1 branch of the trigeminal nerve on the left frontoparietal scalp following an HZ outbreak in a 49-year-old woman. Skin biopsies were consistent with this diagnosis, which revealed no neuronal innervation of the affected scalp despite intractable itching and chronic pain. Further research of TTS and postherpetic neuralgia is necessary to find appropriate treatment for patients with these conditions.

Case Report

A 49-year-old woman presented to the dermatology department with a concern of itching distributed along the V1 branch of the trigeminal nerve on the left frontoparietal scalp following a herpes zoster (HZ) outbreak in the same dermatome 2 months prior. She initially presented to the emergency department 2 months earlier with vesicular lesions distributed along the V1 branch of the trigeminal nerve, along with facial swelling, periorbital edema, inability to open the left eye, and “excruciating” pain. Her left eye was “itchy” but no ophthalmologic pathology was noted on examination. She was diagnosed with HZ and was treated with valacyclovir and prednisone. Oxycodone-acetaminophen followed by hydromorphone was prescribed for the severe pain with limited benefit. After completing treatment with valacyclovir, oral gabapentin was added for additional pain management, with an initial dose of 100 mg 3 times daily.

At the current presentation, the patient reported profound pruritus in the left frontoparietal scalp region that was intractable and debilitating. Some improvement of the itching was achieved with scratching that resulted in deep ulcerations of the scalp with moderate associated pain. In addition to the prior HZ outbreak, her medical history was remarkable for recurrent lymphoma, uterine cancer, chronic bronchitis, depression, hypothyroidism, osteoarthritis, and primary varicella-zoster virus infection in childhood. Her current medications included oral gabapentin (600 mg 3 times daily), diphenhydramine, levothyroxine, simvastatin, and topical ointments for itching.

On dermatologic evaluation, the patient rated her pain as a 5 on a 10-point scale of intensity. Alopecia involving the left frontoparietal scalp with a 2×3-cm ulceration in a geometric pattern with surrounding erythema was noted (Figure 1A). There also was hyperpigmentation on the forehead distributed along the V1 branch of the trigeminal nerve (Figure 1B). The patient also had been seen in the pain clinic where examination revealed sensory loss to both light touch and sharp stimulus along the left V1 branch of the trigeminal nerve. Visual fields were full, ocular movements were intact, and the face was symmetric with lower cranial nerves intact.

Figure 1. Alopecia involving the left frontoparietal scalp with a 2×3-cm ulceration in a geometric pattern with surrounding erythema (A). Hyperpigmentation distributed along the V1 branch of the trigeminal nerve due to postinflammatory changes following herpes zoster infection in the same dermatome (B).

A diagnosis of trigeminal trophic syndrome (TTS) with chronic pain and pruritus due to a complex sensory neural disorder associated with HZ reactivation was made. Treatment included an increase in the dosage of oral gabapentin (1200 mg 3 times daily), oral oxycodone (5 mg every 4 to 6 hours as needed), and sphenopalatine ganglion block on the left side in an attempt to decrease pain and pruritus. At 6-week follow-up, the patient had no improvement in symptoms.

Three scalp punch biopsies were performed on presentation to the dermatology clinic including 2 from the affected area on the left frontoparietal scalp, and one from normal skin on the right side to assess the small nerve fibers affected. Protein gene product 9.5 (PGP 9.5) immunostaining was performed to assess epidermal nerve fiber density. The left scalp biopsies were consistent with a complete focal sensory neuropathy affecting sensory and autonomic axons (Figure 2A). The right scalp biopsy revealed well-innervated skin (Figure 2B).

Figure 2. Fluorescent labeling with protein gene product 9.5 allowed for comparison of epidermal small nerve fibers on the affected (left) and unaffected (right) sides of the scalp. A biopsy of the left side of the scalp was consistent with a complete focal sensory neuropathy affecting sensory and autonomic axons, and complete absence of epidermal nerve fibers and subepidermal nerve plexus were seen (A)(original magnification ×20). On the right side of the scalp, well-innervated epidermal nerve fibers (white arrows) and subepidermal nerve plexus (green arrow) were seen (B)(original magnification ×20).

One year after the original HZ outbreak, the patient continued to have debilitating pruritus and pain in the affected dermatome. On physical examination at 1-year follow-up, the hyperpigmentation on the left side of the forehead showed minimal improvement. The ulcerations were healed, but excoriations were noted in the area. Having experienced some relief from titration of the dose of gabapentin 800 mg 3 times daily and doxepin 25 mg nightly at 1-year follow-up, the patient returned to work but remained highly distressed by her symptoms. Neurosurgery was consulted for possible balloon rhizotomy of the left trigeminal nerve, which she ultimately refused due to concerns about side effects.

Comment

Trophic trigeminal syndrome is characterized by unilateral ulceration of the face with anesthesia, paresthesia, and a crescent-shaped erosion or ulcer.^1,2 It is one of 2 causes of self-induced facial ulcerations, the other being factitial dermatitis.^1,3,4 A 2008 retrospective medical chart review and report of 14 cases helped elucidate the epidemiology of TTS.² In this case series, the female to male ratio was 6 to 1, and the mean age of TTS onset was 45 years (age range, 6–82 years). The cause of disease in most patients was iatrogenic and the latent period to onset ranged from days to almost one decade. Most patients self-manipulated the face (n=9), and most ulcers affected the second trigeminal division. Pain intensity was severe in most (n=6), and gabapentin offered relief in only 2 cases.²

The etiologies of TTS are wide ranging, and the differential diagnosis should be contemplated when patients present with facial ulcers. Most cases are iatrogenic secondary to trigeminal rhizotomy,⁵ alcohol injections into the gasserian ganglion, or electrocoagulation. Also common are cases caused by ischemic damage to the trigeminal ganglion⁶ or Wallenberg syndrome.⁷ More rare etiologies include trauma,⁷ craniotomy,⁷ astrocytoma, acoustic neuroma, meningioma,⁸ idiopathic causes, basal cell carcinoma, infectious diseases (eg, tertiary syphilis, recurrent herpes simplex virus, leishmaniasis, cutaneous tuberculosis, leprosy, HZ),^9-11 or systemic disease (eg, Wegener granulomatosis, Horton arteritis).

Trigeminal trophic syndrome is rare and there is little agreement on a treatment algorithm. As in our case, a methodical trial-and-error approach is suggested while encouraging the patient not to abandon treatment when efforts are not fruitful. The most important treatment strategy is behavioral modification; patients must become aware of the role of self-manipulation and assiduously avoid it. Using occlusive dressings at the affected site also may be helpful^3,12 Transcutaneous electrical nerve stimulation may lead to improvement, but relapse is common with treatment discontinuation. Therapies directed at reducing paresthesia (eg, carbamazepine, diazepam, amitriptyline, chlorpromazine, pimozide) are sometimes successful, but relapse is common.^1,3 Transplantation of in vitro–cultured epidermal cells is a new experimental treatment that offers hope for future success.¹³ Facial reconstruction of the affected area may help patients who can restrain themselves from self-manipulation.⁴

Skin biopsy findings in our case revealed an interesting aspect of the disease process of TTS. Skin biopsies are helpful in ruling out malignancy and specific stains can be used to further elucidate disease or pathologic processes occurring in the skin. In TTS, no specific changes are seen on hematoxylin and eosin staining, revealing only nonspecific inflammatory changes.^1,5 Strikingly, the pathology of affected skin in patients with postherpetic neuralgia often reveals distal nociceptive axon loss,⁹ as was seen in the skin biopsies from our patient’s left scalp. It has been proven by many researchers in many neuropathic pain conditions that the pathological signature of chronic neuropathic pain is reduction in the density of cutaneous nociceptive innervation.⁹ The most common method for visualizing cutaneous neuritis is using an immunohistochemical labeling method in which antibodies are directed against PGP 9.5. A pan-axonal neurofilament marker, PGP 9.5 allows for visualization of small sensory nerve endings in the skin. As nociceptive axons degenerate in neuropathic pain conditions, it is believed that initiation of proalgesic changes within remaining peripheral nerves and the central nervous system (CNS) occur. Another interesting aspect of our case was the patient’s persistent intractable itching and chronic pain 2 months following the initial HZ outbreak. Although pain and itching can be evoked by similar stimuli and injuries, it has been shown that both have separate neuronal pathways because they produce different conscious and reflex motor actions.¹⁴ For instance, pain causes a withdrawal reflex, while itching causes mechanical stimulation of the affected area. The act of itching is thought to have evolved to protect against threats by the act of dislodging the stimulus rather than withdrawing as seen in pain.¹⁴ It has been hypothesized that postherpetic itching (chronic pruritus following an HZ outbreak) is due to spontaneous firing of denervated CNS itch neurons.⁹

Postherpetic neuralgia–related pain seems to be most closely correlated with degeneration of varicella-zoster virus–infected primary afferent neurons. With deceased afferent neurons sending signals to the CNS and death or dysfunction of inhibitory interneurons in the dorsal horn of the spinal cord due to peripheral nerve injury, there is increased paradoxical electrical activity in specific CNS neurons. This CNS plasticity results in neuropathic pain and other altered sensory abnormalities in patients with TTS.⁹

Conclusion

We present a case of TTS distributed along the V1 branch of the trigeminal nerve on the left frontoparietal scalp following an HZ outbreak in a 49-year-old woman. Skin biopsies were consistent with this diagnosis, which revealed no neuronal innervation of the affected scalp despite intractable itching and chronic pain. Further research of TTS and postherpetic neuralgia is necessary to find appropriate treatment for patients with these conditions.

Case Report

A 49-year-old woman presented to the dermatology department with a concern of itching distributed along the V1 branch of the trigeminal nerve on the left frontoparietal scalp following a herpes zoster (HZ) outbreak in the same dermatome 2 months prior. She initially presented to the emergency department 2 months earlier with vesicular lesions distributed along the V1 branch of the trigeminal nerve, along with facial swelling, periorbital edema, inability to open the left eye, and “excruciating” pain. Her left eye was “itchy” but no ophthalmologic pathology was noted on examination. She was diagnosed with HZ and was treated with valacyclovir and prednisone. Oxycodone-acetaminophen followed by hydromorphone was prescribed for the severe pain with limited benefit. After completing treatment with valacyclovir, oral gabapentin was added for additional pain management, with an initial dose of 100 mg 3 times daily.

At the current presentation, the patient reported profound pruritus in the left frontoparietal scalp region that was intractable and debilitating. Some improvement of the itching was achieved with scratching that resulted in deep ulcerations of the scalp with moderate associated pain. In addition to the prior HZ outbreak, her medical history was remarkable for recurrent lymphoma, uterine cancer, chronic bronchitis, depression, hypothyroidism, osteoarthritis, and primary varicella-zoster virus infection in childhood. Her current medications included oral gabapentin (600 mg 3 times daily), diphenhydramine, levothyroxine, simvastatin, and topical ointments for itching.

On dermatologic evaluation, the patient rated her pain as a 5 on a 10-point scale of intensity. Alopecia involving the left frontoparietal scalp with a 2×3-cm ulceration in a geometric pattern with surrounding erythema was noted (Figure 1A). There also was hyperpigmentation on the forehead distributed along the V1 branch of the trigeminal nerve (Figure 1B). The patient also had been seen in the pain clinic where examination revealed sensory loss to both light touch and sharp stimulus along the left V1 branch of the trigeminal nerve. Visual fields were full, ocular movements were intact, and the face was symmetric with lower cranial nerves intact.

Figure 1. Alopecia involving the left frontoparietal scalp with a 2×3-cm ulceration in a geometric pattern with surrounding erythema (A). Hyperpigmentation distributed along the V1 branch of the trigeminal nerve due to postinflammatory changes following herpes zoster infection in the same dermatome (B).

A diagnosis of trigeminal trophic syndrome (TTS) with chronic pain and pruritus due to a complex sensory neural disorder associated with HZ reactivation was made. Treatment included an increase in the dosage of oral gabapentin (1200 mg 3 times daily), oral oxycodone (5 mg every 4 to 6 hours as needed), and sphenopalatine ganglion block on the left side in an attempt to decrease pain and pruritus. At 6-week follow-up, the patient had no improvement in symptoms.

Three scalp punch biopsies were performed on presentation to the dermatology clinic including 2 from the affected area on the left frontoparietal scalp, and one from normal skin on the right side to assess the small nerve fibers affected. Protein gene product 9.5 (PGP 9.5) immunostaining was performed to assess epidermal nerve fiber density. The left scalp biopsies were consistent with a complete focal sensory neuropathy affecting sensory and autonomic axons (Figure 2A). The right scalp biopsy revealed well-innervated skin (Figure 2B).

Figure 2. Fluorescent labeling with protein gene product 9.5 allowed for comparison of epidermal small nerve fibers on the affected (left) and unaffected (right) sides of the scalp. A biopsy of the left side of the scalp was consistent with a complete focal sensory neuropathy affecting sensory and autonomic axons, and complete absence of epidermal nerve fibers and subepidermal nerve plexus were seen (A)(original magnification ×20). On the right side of the scalp, well-innervated epidermal nerve fibers (white arrows) and subepidermal nerve plexus (green arrow) were seen (B)(original magnification ×20).

One year after the original HZ outbreak, the patient continued to have debilitating pruritus and pain in the affected dermatome. On physical examination at 1-year follow-up, the hyperpigmentation on the left side of the forehead showed minimal improvement. The ulcerations were healed, but excoriations were noted in the area. Having experienced some relief from titration of the dose of gabapentin 800 mg 3 times daily and doxepin 25 mg nightly at 1-year follow-up, the patient returned to work but remained highly distressed by her symptoms. Neurosurgery was consulted for possible balloon rhizotomy of the left trigeminal nerve, which she ultimately refused due to concerns about side effects.

Comment

Trophic trigeminal syndrome is characterized by unilateral ulceration of the face with anesthesia, paresthesia, and a crescent-shaped erosion or ulcer.^1,2 It is one of 2 causes of self-induced facial ulcerations, the other being factitial dermatitis.^1,3,4 A 2008 retrospective medical chart review and report of 14 cases helped elucidate the epidemiology of TTS.² In this case series, the female to male ratio was 6 to 1, and the mean age of TTS onset was 45 years (age range, 6–82 years). The cause of disease in most patients was iatrogenic and the latent period to onset ranged from days to almost one decade. Most patients self-manipulated the face (n=9), and most ulcers affected the second trigeminal division. Pain intensity was severe in most (n=6), and gabapentin offered relief in only 2 cases.²

The etiologies of TTS are wide ranging, and the differential diagnosis should be contemplated when patients present with facial ulcers. Most cases are iatrogenic secondary to trigeminal rhizotomy,⁵ alcohol injections into the gasserian ganglion, or electrocoagulation. Also common are cases caused by ischemic damage to the trigeminal ganglion⁶ or Wallenberg syndrome.⁷ More rare etiologies include trauma,⁷ craniotomy,⁷ astrocytoma, acoustic neuroma, meningioma,⁸ idiopathic causes, basal cell carcinoma, infectious diseases (eg, tertiary syphilis, recurrent herpes simplex virus, leishmaniasis, cutaneous tuberculosis, leprosy, HZ),^9-11 or systemic disease (eg, Wegener granulomatosis, Horton arteritis).

Trigeminal trophic syndrome is rare and there is little agreement on a treatment algorithm. As in our case, a methodical trial-and-error approach is suggested while encouraging the patient not to abandon treatment when efforts are not fruitful. The most important treatment strategy is behavioral modification; patients must become aware of the role of self-manipulation and assiduously avoid it. Using occlusive dressings at the affected site also may be helpful^3,12 Transcutaneous electrical nerve stimulation may lead to improvement, but relapse is common with treatment discontinuation. Therapies directed at reducing paresthesia (eg, carbamazepine, diazepam, amitriptyline, chlorpromazine, pimozide) are sometimes successful, but relapse is common.^1,3 Transplantation of in vitro–cultured epidermal cells is a new experimental treatment that offers hope for future success.¹³ Facial reconstruction of the affected area may help patients who can restrain themselves from self-manipulation.⁴

Skin biopsy findings in our case revealed an interesting aspect of the disease process of TTS. Skin biopsies are helpful in ruling out malignancy and specific stains can be used to further elucidate disease or pathologic processes occurring in the skin. In TTS, no specific changes are seen on hematoxylin and eosin staining, revealing only nonspecific inflammatory changes.^1,5 Strikingly, the pathology of affected skin in patients with postherpetic neuralgia often reveals distal nociceptive axon loss,⁹ as was seen in the skin biopsies from our patient’s left scalp. It has been proven by many researchers in many neuropathic pain conditions that the pathological signature of chronic neuropathic pain is reduction in the density of cutaneous nociceptive innervation.⁹ The most common method for visualizing cutaneous neuritis is using an immunohistochemical labeling method in which antibodies are directed against PGP 9.5. A pan-axonal neurofilament marker, PGP 9.5 allows for visualization of small sensory nerve endings in the skin. As nociceptive axons degenerate in neuropathic pain conditions, it is believed that initiation of proalgesic changes within remaining peripheral nerves and the central nervous system (CNS) occur. Another interesting aspect of our case was the patient’s persistent intractable itching and chronic pain 2 months following the initial HZ outbreak. Although pain and itching can be evoked by similar stimuli and injuries, it has been shown that both have separate neuronal pathways because they produce different conscious and reflex motor actions.¹⁴ For instance, pain causes a withdrawal reflex, while itching causes mechanical stimulation of the affected area. The act of itching is thought to have evolved to protect against threats by the act of dislodging the stimulus rather than withdrawing as seen in pain.¹⁴ It has been hypothesized that postherpetic itching (chronic pruritus following an HZ outbreak) is due to spontaneous firing of denervated CNS itch neurons.⁹

Postherpetic neuralgia–related pain seems to be most closely correlated with degeneration of varicella-zoster virus–infected primary afferent neurons. With deceased afferent neurons sending signals to the CNS and death or dysfunction of inhibitory interneurons in the dorsal horn of the spinal cord due to peripheral nerve injury, there is increased paradoxical electrical activity in specific CNS neurons. This CNS plasticity results in neuropathic pain and other altered sensory abnormalities in patients with TTS.⁹

Conclusion

We present a case of TTS distributed along the V1 branch of the trigeminal nerve on the left frontoparietal scalp following an HZ outbreak in a 49-year-old woman. Skin biopsies were consistent with this diagnosis, which revealed no neuronal innervation of the affected scalp despite intractable itching and chronic pain. Further research of TTS and postherpetic neuralgia is necessary to find appropriate treatment for patients with these conditions.

Glatiramer acetate (GA), a synthetic polypeptide that is injected subcutaneously, has proven effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) and is now considered a first-line agent in the treatment of this condition. Adverse effects associated with GA primarily include local injection-site reactions (LISRs)(eg, erythema, pruritus, burning, pain, inflammation). Transient acute systemic reactions such as flushing and dyspnea also are commonly reported. Lipoatrophy at the injection site frequently has been reported in the literature as a cutaneous adverse effect of GA, but lobular panniculitis and necrosis at the site of injection rarely have been noted.

We report the case of a 36-year-old woman who experienced a severe adverse reaction to a single injection of GA after nearly 1 year of daily use to control symptoms of RRMS. Review of the current literature revealed few reports of the severe reaction of panniculitis and necrosis occurring at the injection site of GA.

Case Report

A 36-year-old woman was referred by her neurologist to the emergency department of our institution’s allergy and immunology clinic for treatment of an allergic reaction to a 20-mg GA injection, which she had been receiving daily for nearly 1 year as therapy for RRMS. A nodule immediately formed at the injection site and eventually became ulcerated. The patient also reported intense chest tightness, shortness of breath, and flushing following the injection. Physical examination revealed a large 8- to 9-cm erythematous area at the injection site on the left buttock. Necrosis and eschar formation also were evident (Figure 1).

Figure 1. Panniculitis with central ulceration and necrosis at the site of a glatiramer acetate injection on the left buttock (A). Closer view of an irregularly shaped necrotic lesion with surrounding erythema (B).

A punch biopsy from the edge of the lesion revealed predominantly lobular panniculitis (Figure 2A) with fat necrosis and numerous foamy macrophages (Figures 2B and 2C). Scattered lymphocytes also were present but no neutrophils or eosinophils were noted (Figure 2B). Interlobular septa were widened secondary to fibrosis (Figure 2A). No lymphoid follicles were identified. A subcutaneous artery was sampled but was negative for vasculitis (Figure 2D).

Figure 2. Lobular panniculitis with fat necrosis, foamy macrophages, and scattered lymphocytes. Septa were widened (A)(H&E, original magnification ×4). Fat necrosis and foamy macrophages were seen (B)(H&E, original magnification ×10). High-power field revealed foamy macrophages (black arrow)(C)(H&E, original magnification ×100). A subcutaneous artery (lower left) was negative for vasculitis (D)(H&E, original magnification ×20).

The necrotic lesion on the left buttock was present for more than 2 months before complete healing occurred. The patient had a history of intolerance or unresponsiveness to all prior medications for RRMS. Several years prior she responded well to treatment with GA for a few months and had been responding well to the injections over the last year. Incremental challenge testing with GA for desensitization was offered to the patient, but she declined treatment out of fear of a recurrent episode, particularly the severe systemic symptoms she had experienced. Unfortunately, she was lost to follow-up.

Comment

Glatiramer acetate, formerly known as copolymer-1, is a first-line treatment of patients with RRMS.¹ Daily administration of subcutaneous injections of GA (20 mg/mL) has proven effective in relapse rate reduction and reduced morbidity in patients with RRMS.² Long-term studies support a relapse rate reduction of more than 50% in patients using GA.³ The most common adverse effects are LISRs.² Systemic reactions following GA injection also are common. A much less common reaction is panniculitis followed by lipoatrophy and/or skin necrosis. Only a few instances of panniculitis-associated necrosis have been reported.

The occurrence of LISRs was reported in 20% to 90% of patients using GA to control RRMS.^2,4 Local injection-site reactions typically resolve within hours to days and have been reported to decrease in frequency over time.⁵ Acute systemic reactions (eg, anxiety, flushing, palpitations, dyspnea) to GA injection are described in approximately 15% of patients.⁶ Systemic reactions usually resolve in 5 to 15 minutes but can last for more than 1 hour.⁵ These reactions are mostly benign and generally are not considered to be allergic or anaphylactic in nature. True systemic anaphylaxis associated with administration of GA is extremely rare.⁷

Lipoatrophy, or localized loss of subcutaneous adipose tissue without evidence of inflammation, has been reported fairly frequently in association with GA (up to 45% of patients receiving GA injections).^2,6,8,9 Lipoatrophy also has been seen following subcutaneous injection of many other drugs, including steroids and insulin. Unlike LISRs, the likelihood of developing lipoatrophy at the injection site increases with longer durations of GA injections.⁵ Lipoatrophy also develops following panniculitis at the site of GA injection.

Based on a search of the MeSH (Medical Subject Headings) database using the terms panniculitis and glatiramer acetate, there only are 10 reported cases of panniculitis as an adverse effect of GA injections.^2,6,10 Lesions were described as either subcutaneous erythematous nodules or atrophic areas that demonstrated panniculitis on histologic examination. Injections preceding the development of panniculitis often were described as remarkably painful.⁴ Residual lipoatrophy and/or hyperpigmentation at the site of panniculitis development is common.² It has been suggested that GA-induced panniculitis may be an early underlying mechanism for the development of lipoatrophy, and thus may be more common than originally suspected.¹⁰

Histopathologic examination of GA-induced panniculitis typically reveals a localized, mostly lobular, panniculitis with lipophagic granulomas, lymphocytes, and thickened septa. The lipophagic granulomas (a characteristic finding in panniculitis) form from local macrophages that engulf the lipids released from necrotic adipocytes.¹¹ A large, pale, granular or vacuolated cytoplasm typically can be observed on microscopic examination of the macrophages (Figure 2C). Connective tissue septa typically are widened with cell infiltrates, usually lymphocytes. Other cell types, including macrophages, eosinophils, and neutrophils, also have been identified in both the septa and fat lobules. These histologic elements may change and evolve over time.

Necrosis in association with panniculitis, as seen in our patient, rarely has been reported.^4,12 All of the necrotic reactions described occurred after at least 1 year of GA therapy and took several weeks to resolve.^4,12 When presented with the development of skin necrosis at the site of GA injection, it is essential to distinguish between an adverse effect associated with the drug itself and Nicolau syndrome (embolia cutis medicamentosa).¹³ Necrosis at multiple injection sites or recurrence with later injections supports a GA-specific effect.¹²

Nicolau syndrome is a well-known traumatic reaction that leads to microembolization and resultant vasospasm as well as necrosis throughout the skin and possibly the underlying muscular layer.¹⁴ Although more commonly associated with intramuscular injections, Nicolau syndrome has been described with subcutaneous injections of GA in a few rare instances.^13,15 Because of the associated severe systemic reaction as well as the histologic examination (Figure 2D), we believe the skin necrosis seen in our patient was from a reaction to GA rather than Nicolau syndrome. Our patient was not interested in restarting GA therapy; therefore, it is unknown if this reaction would have recurred, but we suspect high probability of recurrence without desensitization attempts.

Preventative measures can be taken to decrease the risk for LISRs, and patients should be educated on these techniques. Applying ice to the injection site for at least 30 seconds before cleaning the skin for injection may reduce local adverse effects.⁴ Proper instruction on injection techniques should be provided by a knowledgeable health care professional and topical anesthetics and/or steroids may be offered to reduce pain associated with injection. There have been no proven measures for prevention of lipoatrophy, panniculitis, or necrosis, and these adverse effects are not thought to be attributed to improper injection techniques.¹⁴ Rotation of injection sites is the only suggested means of decreasing the potential risk for more severely and permanently disfiguring local reactions.

If panniculitis following GA injection is suspected, a large biopsy that encompasses the entire subcutaneous fat layer is necessary for proper dermatopathologic classification.¹¹ Glatiramer acetate injections should be stopped immediately. These reactions disappear when the injections are stopped but recur when restarting treatment.² The efficacy of GA in the treatment of RRMS has led to the possible use of this drug in the treatment of other autoimmune diseases.¹⁶ Thus, it is important for clinicians to be aware of all adverse effects of subcutaneous injections of GA, including the rare occurrence of panniculitis and necrosis, and when discontinuation of therapy is indicated.

Conclusion

Daily subcutaneous injection of GA for the treatment of RRMS can result in the rare but characteristic development of localized panniculitis and necrosis. Glatiramer acetate is a common and highly effective therapy used for the treatment of RRMS. Common adverse effects include LISRs and transient acute systemic reactions. Less commonly observed but characteristic of GA injections is localized lipoatrophy and mostly lobular panniculitis. Necrosis rarely can develop in association with these cutaneous reactions. It is essential to differentiate between necrosis secondary to Nicolau syndrome and skin necrosis as a unique reaction to GA; the latter is an indication for discontinuation of GA injections. Dermatologists should be made aware of adverse cutaneous reactions seen with GA therapy, especially with the potential for expansion of the use of GA to treat other autoimmune processes. Further research is needed regarding the histopathologic evolution and mechanisms behind the development of lipoatrophy, panniculitis, and necrosis at the site of GA injection.

Glatiramer acetate (GA), a synthetic polypeptide that is injected subcutaneously, has proven effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) and is now considered a first-line agent in the treatment of this condition. Adverse effects associated with GA primarily include local injection-site reactions (LISRs)(eg, erythema, pruritus, burning, pain, inflammation). Transient acute systemic reactions such as flushing and dyspnea also are commonly reported. Lipoatrophy at the injection site frequently has been reported in the literature as a cutaneous adverse effect of GA, but lobular panniculitis and necrosis at the site of injection rarely have been noted.

We report the case of a 36-year-old woman who experienced a severe adverse reaction to a single injection of GA after nearly 1 year of daily use to control symptoms of RRMS. Review of the current literature revealed few reports of the severe reaction of panniculitis and necrosis occurring at the injection site of GA.

Case Report

A 36-year-old woman was referred by her neurologist to the emergency department of our institution’s allergy and immunology clinic for treatment of an allergic reaction to a 20-mg GA injection, which she had been receiving daily for nearly 1 year as therapy for RRMS. A nodule immediately formed at the injection site and eventually became ulcerated. The patient also reported intense chest tightness, shortness of breath, and flushing following the injection. Physical examination revealed a large 8- to 9-cm erythematous area at the injection site on the left buttock. Necrosis and eschar formation also were evident (Figure 1).

Figure 1. Panniculitis with central ulceration and necrosis at the site of a glatiramer acetate injection on the left buttock (A). Closer view of an irregularly shaped necrotic lesion with surrounding erythema (B).

A punch biopsy from the edge of the lesion revealed predominantly lobular panniculitis (Figure 2A) with fat necrosis and numerous foamy macrophages (Figures 2B and 2C). Scattered lymphocytes also were present but no neutrophils or eosinophils were noted (Figure 2B). Interlobular septa were widened secondary to fibrosis (Figure 2A). No lymphoid follicles were identified. A subcutaneous artery was sampled but was negative for vasculitis (Figure 2D).

Figure 2. Lobular panniculitis with fat necrosis, foamy macrophages, and scattered lymphocytes. Septa were widened (A)(H&E, original magnification ×4). Fat necrosis and foamy macrophages were seen (B)(H&E, original magnification ×10). High-power field revealed foamy macrophages (black arrow)(C)(H&E, original magnification ×100). A subcutaneous artery (lower left) was negative for vasculitis (D)(H&E, original magnification ×20).

The necrotic lesion on the left buttock was present for more than 2 months before complete healing occurred. The patient had a history of intolerance or unresponsiveness to all prior medications for RRMS. Several years prior she responded well to treatment with GA for a few months and had been responding well to the injections over the last year. Incremental challenge testing with GA for desensitization was offered to the patient, but she declined treatment out of fear of a recurrent episode, particularly the severe systemic symptoms she had experienced. Unfortunately, she was lost to follow-up.

Comment

Glatiramer acetate, formerly known as copolymer-1, is a first-line treatment of patients with RRMS.¹ Daily administration of subcutaneous injections of GA (20 mg/mL) has proven effective in relapse rate reduction and reduced morbidity in patients with RRMS.² Long-term studies support a relapse rate reduction of more than 50% in patients using GA.³ The most common adverse effects are LISRs.² Systemic reactions following GA injection also are common. A much less common reaction is panniculitis followed by lipoatrophy and/or skin necrosis. Only a few instances of panniculitis-associated necrosis have been reported.

The occurrence of LISRs was reported in 20% to 90% of patients using GA to control RRMS.^2,4 Local injection-site reactions typically resolve within hours to days and have been reported to decrease in frequency over time.⁵ Acute systemic reactions (eg, anxiety, flushing, palpitations, dyspnea) to GA injection are described in approximately 15% of patients.⁶ Systemic reactions usually resolve in 5 to 15 minutes but can last for more than 1 hour.⁵ These reactions are mostly benign and generally are not considered to be allergic or anaphylactic in nature. True systemic anaphylaxis associated with administration of GA is extremely rare.⁷

Lipoatrophy, or localized loss of subcutaneous adipose tissue without evidence of inflammation, has been reported fairly frequently in association with GA (up to 45% of patients receiving GA injections).^2,6,8,9 Lipoatrophy also has been seen following subcutaneous injection of many other drugs, including steroids and insulin. Unlike LISRs, the likelihood of developing lipoatrophy at the injection site increases with longer durations of GA injections.⁵ Lipoatrophy also develops following panniculitis at the site of GA injection.

Based on a search of the MeSH (Medical Subject Headings) database using the terms panniculitis and glatiramer acetate, there only are 10 reported cases of panniculitis as an adverse effect of GA injections.^2,6,10 Lesions were described as either subcutaneous erythematous nodules or atrophic areas that demonstrated panniculitis on histologic examination. Injections preceding the development of panniculitis often were described as remarkably painful.⁴ Residual lipoatrophy and/or hyperpigmentation at the site of panniculitis development is common.² It has been suggested that GA-induced panniculitis may be an early underlying mechanism for the development of lipoatrophy, and thus may be more common than originally suspected.¹⁰

Histopathologic examination of GA-induced panniculitis typically reveals a localized, mostly lobular, panniculitis with lipophagic granulomas, lymphocytes, and thickened septa. The lipophagic granulomas (a characteristic finding in panniculitis) form from local macrophages that engulf the lipids released from necrotic adipocytes.¹¹ A large, pale, granular or vacuolated cytoplasm typically can be observed on microscopic examination of the macrophages (Figure 2C). Connective tissue septa typically are widened with cell infiltrates, usually lymphocytes. Other cell types, including macrophages, eosinophils, and neutrophils, also have been identified in both the septa and fat lobules. These histologic elements may change and evolve over time.

Necrosis in association with panniculitis, as seen in our patient, rarely has been reported.^4,12 All of the necrotic reactions described occurred after at least 1 year of GA therapy and took several weeks to resolve.^4,12 When presented with the development of skin necrosis at the site of GA injection, it is essential to distinguish between an adverse effect associated with the drug itself and Nicolau syndrome (embolia cutis medicamentosa).¹³ Necrosis at multiple injection sites or recurrence with later injections supports a GA-specific effect.¹²

Nicolau syndrome is a well-known traumatic reaction that leads to microembolization and resultant vasospasm as well as necrosis throughout the skin and possibly the underlying muscular layer.¹⁴ Although more commonly associated with intramuscular injections, Nicolau syndrome has been described with subcutaneous injections of GA in a few rare instances.^13,15 Because of the associated severe systemic reaction as well as the histologic examination (Figure 2D), we believe the skin necrosis seen in our patient was from a reaction to GA rather than Nicolau syndrome. Our patient was not interested in restarting GA therapy; therefore, it is unknown if this reaction would have recurred, but we suspect high probability of recurrence without desensitization attempts.

Preventative measures can be taken to decrease the risk for LISRs, and patients should be educated on these techniques. Applying ice to the injection site for at least 30 seconds before cleaning the skin for injection may reduce local adverse effects.⁴ Proper instruction on injection techniques should be provided by a knowledgeable health care professional and topical anesthetics and/or steroids may be offered to reduce pain associated with injection. There have been no proven measures for prevention of lipoatrophy, panniculitis, or necrosis, and these adverse effects are not thought to be attributed to improper injection techniques.¹⁴ Rotation of injection sites is the only suggested means of decreasing the potential risk for more severely and permanently disfiguring local reactions.

If panniculitis following GA injection is suspected, a large biopsy that encompasses the entire subcutaneous fat layer is necessary for proper dermatopathologic classification.¹¹ Glatiramer acetate injections should be stopped immediately. These reactions disappear when the injections are stopped but recur when restarting treatment.² The efficacy of GA in the treatment of RRMS has led to the possible use of this drug in the treatment of other autoimmune diseases.¹⁶ Thus, it is important for clinicians to be aware of all adverse effects of subcutaneous injections of GA, including the rare occurrence of panniculitis and necrosis, and when discontinuation of therapy is indicated.

Conclusion

Daily subcutaneous injection of GA for the treatment of RRMS can result in the rare but characteristic development of localized panniculitis and necrosis. Glatiramer acetate is a common and highly effective therapy used for the treatment of RRMS. Common adverse effects include LISRs and transient acute systemic reactions. Less commonly observed but characteristic of GA injections is localized lipoatrophy and mostly lobular panniculitis. Necrosis rarely can develop in association with these cutaneous reactions. It is essential to differentiate between necrosis secondary to Nicolau syndrome and skin necrosis as a unique reaction to GA; the latter is an indication for discontinuation of GA injections. Dermatologists should be made aware of adverse cutaneous reactions seen with GA therapy, especially with the potential for expansion of the use of GA to treat other autoimmune processes. Further research is needed regarding the histopathologic evolution and mechanisms behind the development of lipoatrophy, panniculitis, and necrosis at the site of GA injection.

Glatiramer acetate (GA), a synthetic polypeptide that is injected subcutaneously, has proven effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) and is now considered a first-line agent in the treatment of this condition. Adverse effects associated with GA primarily include local injection-site reactions (LISRs)(eg, erythema, pruritus, burning, pain, inflammation). Transient acute systemic reactions such as flushing and dyspnea also are commonly reported. Lipoatrophy at the injection site frequently has been reported in the literature as a cutaneous adverse effect of GA, but lobular panniculitis and necrosis at the site of injection rarely have been noted.

We report the case of a 36-year-old woman who experienced a severe adverse reaction to a single injection of GA after nearly 1 year of daily use to control symptoms of RRMS. Review of the current literature revealed few reports of the severe reaction of panniculitis and necrosis occurring at the injection site of GA.

Case Report

A 36-year-old woman was referred by her neurologist to the emergency department of our institution’s allergy and immunology clinic for treatment of an allergic reaction to a 20-mg GA injection, which she had been receiving daily for nearly 1 year as therapy for RRMS. A nodule immediately formed at the injection site and eventually became ulcerated. The patient also reported intense chest tightness, shortness of breath, and flushing following the injection. Physical examination revealed a large 8- to 9-cm erythematous area at the injection site on the left buttock. Necrosis and eschar formation also were evident (Figure 1).

Figure 1. Panniculitis with central ulceration and necrosis at the site of a glatiramer acetate injection on the left buttock (A). Closer view of an irregularly shaped necrotic lesion with surrounding erythema (B).

A punch biopsy from the edge of the lesion revealed predominantly lobular panniculitis (Figure 2A) with fat necrosis and numerous foamy macrophages (Figures 2B and 2C). Scattered lymphocytes also were present but no neutrophils or eosinophils were noted (Figure 2B). Interlobular septa were widened secondary to fibrosis (Figure 2A). No lymphoid follicles were identified. A subcutaneous artery was sampled but was negative for vasculitis (Figure 2D).

Figure 2. Lobular panniculitis with fat necrosis, foamy macrophages, and scattered lymphocytes. Septa were widened (A)(H&E, original magnification ×4). Fat necrosis and foamy macrophages were seen (B)(H&E, original magnification ×10). High-power field revealed foamy macrophages (black arrow)(C)(H&E, original magnification ×100). A subcutaneous artery (lower left) was negative for vasculitis (D)(H&E, original magnification ×20).

The necrotic lesion on the left buttock was present for more than 2 months before complete healing occurred. The patient had a history of intolerance or unresponsiveness to all prior medications for RRMS. Several years prior she responded well to treatment with GA for a few months and had been responding well to the injections over the last year. Incremental challenge testing with GA for desensitization was offered to the patient, but she declined treatment out of fear of a recurrent episode, particularly the severe systemic symptoms she had experienced. Unfortunately, she was lost to follow-up.

Comment

Glatiramer acetate, formerly known as copolymer-1, is a first-line treatment of patients with RRMS.¹ Daily administration of subcutaneous injections of GA (20 mg/mL) has proven effective in relapse rate reduction and reduced morbidity in patients with RRMS.² Long-term studies support a relapse rate reduction of more than 50% in patients using GA.³ The most common adverse effects are LISRs.² Systemic reactions following GA injection also are common. A much less common reaction is panniculitis followed by lipoatrophy and/or skin necrosis. Only a few instances of panniculitis-associated necrosis have been reported.

The occurrence of LISRs was reported in 20% to 90% of patients using GA to control RRMS.^2,4 Local injection-site reactions typically resolve within hours to days and have been reported to decrease in frequency over time.⁵ Acute systemic reactions (eg, anxiety, flushing, palpitations, dyspnea) to GA injection are described in approximately 15% of patients.⁶ Systemic reactions usually resolve in 5 to 15 minutes but can last for more than 1 hour.⁵ These reactions are mostly benign and generally are not considered to be allergic or anaphylactic in nature. True systemic anaphylaxis associated with administration of GA is extremely rare.⁷

Lipoatrophy, or localized loss of subcutaneous adipose tissue without evidence of inflammation, has been reported fairly frequently in association with GA (up to 45% of patients receiving GA injections).^2,6,8,9 Lipoatrophy also has been seen following subcutaneous injection of many other drugs, including steroids and insulin. Unlike LISRs, the likelihood of developing lipoatrophy at the injection site increases with longer durations of GA injections.⁵ Lipoatrophy also develops following panniculitis at the site of GA injection.

Based on a search of the MeSH (Medical Subject Headings) database using the terms panniculitis and glatiramer acetate, there only are 10 reported cases of panniculitis as an adverse effect of GA injections.^2,6,10 Lesions were described as either subcutaneous erythematous nodules or atrophic areas that demonstrated panniculitis on histologic examination. Injections preceding the development of panniculitis often were described as remarkably painful.⁴ Residual lipoatrophy and/or hyperpigmentation at the site of panniculitis development is common.² It has been suggested that GA-induced panniculitis may be an early underlying mechanism for the development of lipoatrophy, and thus may be more common than originally suspected.¹⁰

Histopathologic examination of GA-induced panniculitis typically reveals a localized, mostly lobular, panniculitis with lipophagic granulomas, lymphocytes, and thickened septa. The lipophagic granulomas (a characteristic finding in panniculitis) form from local macrophages that engulf the lipids released from necrotic adipocytes.¹¹ A large, pale, granular or vacuolated cytoplasm typically can be observed on microscopic examination of the macrophages (Figure 2C). Connective tissue septa typically are widened with cell infiltrates, usually lymphocytes. Other cell types, including macrophages, eosinophils, and neutrophils, also have been identified in both the septa and fat lobules. These histologic elements may change and evolve over time.

Necrosis in association with panniculitis, as seen in our patient, rarely has been reported.^4,12 All of the necrotic reactions described occurred after at least 1 year of GA therapy and took several weeks to resolve.^4,12 When presented with the development of skin necrosis at the site of GA injection, it is essential to distinguish between an adverse effect associated with the drug itself and Nicolau syndrome (embolia cutis medicamentosa).¹³ Necrosis at multiple injection sites or recurrence with later injections supports a GA-specific effect.¹²

Nicolau syndrome is a well-known traumatic reaction that leads to microembolization and resultant vasospasm as well as necrosis throughout the skin and possibly the underlying muscular layer.¹⁴ Although more commonly associated with intramuscular injections, Nicolau syndrome has been described with subcutaneous injections of GA in a few rare instances.^13,15 Because of the associated severe systemic reaction as well as the histologic examination (Figure 2D), we believe the skin necrosis seen in our patient was from a reaction to GA rather than Nicolau syndrome. Our patient was not interested in restarting GA therapy; therefore, it is unknown if this reaction would have recurred, but we suspect high probability of recurrence without desensitization attempts.

Preventative measures can be taken to decrease the risk for LISRs, and patients should be educated on these techniques. Applying ice to the injection site for at least 30 seconds before cleaning the skin for injection may reduce local adverse effects.⁴ Proper instruction on injection techniques should be provided by a knowledgeable health care professional and topical anesthetics and/or steroids may be offered to reduce pain associated with injection. There have been no proven measures for prevention of lipoatrophy, panniculitis, or necrosis, and these adverse effects are not thought to be attributed to improper injection techniques.¹⁴ Rotation of injection sites is the only suggested means of decreasing the potential risk for more severely and permanently disfiguring local reactions.

If panniculitis following GA injection is suspected, a large biopsy that encompasses the entire subcutaneous fat layer is necessary for proper dermatopathologic classification.¹¹ Glatiramer acetate injections should be stopped immediately. These reactions disappear when the injections are stopped but recur when restarting treatment.² The efficacy of GA in the treatment of RRMS has led to the possible use of this drug in the treatment of other autoimmune diseases.¹⁶ Thus, it is important for clinicians to be aware of all adverse effects of subcutaneous injections of GA, including the rare occurrence of panniculitis and necrosis, and when discontinuation of therapy is indicated.

Conclusion

Daily subcutaneous injection of GA for the treatment of RRMS can result in the rare but characteristic development of localized panniculitis and necrosis. Glatiramer acetate is a common and highly effective therapy used for the treatment of RRMS. Common adverse effects include LISRs and transient acute systemic reactions. Less commonly observed but characteristic of GA injections is localized lipoatrophy and mostly lobular panniculitis. Necrosis rarely can develop in association with these cutaneous reactions. It is essential to differentiate between necrosis secondary to Nicolau syndrome and skin necrosis as a unique reaction to GA; the latter is an indication for discontinuation of GA injections. Dermatologists should be made aware of adverse cutaneous reactions seen with GA therapy, especially with the potential for expansion of the use of GA to treat other autoimmune processes. Further research is needed regarding the histopathologic evolution and mechanisms behind the development of lipoatrophy, panniculitis, and necrosis at the site of GA injection.

Nail matrix biopsies are performed to confirm a diagnosis or surgically remove a skin lesion that is affecting the growth of the nail plate. The procedure may be used to identify:

Nail biopsy can lead to complications such as bleeding, infection, or scarring. Postoperative scarring can cause permanent nail splitting, dystrophy, or both.

In a Cosmetic Dermatology article, “Matrix Biopsy of Longitudinal Melanonychia and Longitudinal Erythronychia: A Step-by-Step Approach,” Drs. Siobhan C. Collins and Nathaniel J. Jellinek review 6 techniques used to biopsy the nail matrix.

Techniques used to biopsy the nail matrix. From Cosmet Dermatol. 2009;22:130-136.

In the setting of longitudinal melanonychia (to diagnose nail melanoma or SCC) and longitudinal erythronychia (to diagnose SCC and rarely amelanotic melanoma or basal cell carcinoma), the techniques they describe accomplish 3 fundamental goals of nail surgery:

Dermatologists must be confident when performing nail biopsies and the techniques discussed by the authors will help approach nail surgery with more certainty.

At the 73rd Annual Meeting of the American Academy of Dermatology, Dr. Jellinek provides a hands-on approach to nail surgery. On Saturday, March 21, he will provide tips for nail surgeries at the “Medical and Surgical Management of Nail Disorders” lecture.

For more information, read the Collins and Jellinek article from Cosmetic Dermatology.

Nail matrix biopsies are performed to confirm a diagnosis or surgically remove a skin lesion that is affecting the growth of the nail plate. The procedure may be used to identify:

Nail biopsy can lead to complications such as bleeding, infection, or scarring. Postoperative scarring can cause permanent nail splitting, dystrophy, or both.

In a Cosmetic Dermatology article, “Matrix Biopsy of Longitudinal Melanonychia and Longitudinal Erythronychia: A Step-by-Step Approach,” Drs. Siobhan C. Collins and Nathaniel J. Jellinek review 6 techniques used to biopsy the nail matrix.

Techniques used to biopsy the nail matrix. From Cosmet Dermatol. 2009;22:130-136.

In the setting of longitudinal melanonychia (to diagnose nail melanoma or SCC) and longitudinal erythronychia (to diagnose SCC and rarely amelanotic melanoma or basal cell carcinoma), the techniques they describe accomplish 3 fundamental goals of nail surgery:

Dermatologists must be confident when performing nail biopsies and the techniques discussed by the authors will help approach nail surgery with more certainty.

At the 73rd Annual Meeting of the American Academy of Dermatology, Dr. Jellinek provides a hands-on approach to nail surgery. On Saturday, March 21, he will provide tips for nail surgeries at the “Medical and Surgical Management of Nail Disorders” lecture.

For more information, read the Collins and Jellinek article from Cosmetic Dermatology.

Nail matrix biopsies are performed to confirm a diagnosis or surgically remove a skin lesion that is affecting the growth of the nail plate. The procedure may be used to identify:

Nail biopsy can lead to complications such as bleeding, infection, or scarring. Postoperative scarring can cause permanent nail splitting, dystrophy, or both.

In a Cosmetic Dermatology article, “Matrix Biopsy of Longitudinal Melanonychia and Longitudinal Erythronychia: A Step-by-Step Approach,” Drs. Siobhan C. Collins and Nathaniel J. Jellinek review 6 techniques used to biopsy the nail matrix.

Techniques used to biopsy the nail matrix. From Cosmet Dermatol. 2009;22:130-136.

In the setting of longitudinal melanonychia (to diagnose nail melanoma or SCC) and longitudinal erythronychia (to diagnose SCC and rarely amelanotic melanoma or basal cell carcinoma), the techniques they describe accomplish 3 fundamental goals of nail surgery:

Dermatologists must be confident when performing nail biopsies and the techniques discussed by the authors will help approach nail surgery with more certainty.

At the 73rd Annual Meeting of the American Academy of Dermatology, Dr. Jellinek provides a hands-on approach to nail surgery. On Saturday, March 21, he will provide tips for nail surgeries at the “Medical and Surgical Management of Nail Disorders” lecture.

For more information, read the Collins and Jellinek article from Cosmetic Dermatology.

A 70-year-old man presented with a nonpruritic erythematous scaly plaque in the left suprapubic region of 6 months’ duration that had failed to respond to terbinafine cream 1% after 1 month of treatment of suspected tinea cruris. His medical history was remarkable for hypertension, hyperlipidemia, chronic obstructive pulmonary disease, benign prostatic hyperplasia, an abdominal aortic aneurysm, alcohol dependence, tobacco use disorder, and unintentional weight loss of 15 lb over the last year.

The Diagnosis: Extramammary Paget Disease

A biopsy of the plaque revealed an intraepidermal proliferation of large cells with abundant clear cytoplasm and large vesicular nuclei distributed throughout the epidermis (Figure 1). The neoplastic cells stained positive for both periodic acid–Schiff stain (Figure 2) and CK7 (Figure 3). Chemistry and liver function panel, urine analysis, carcinoembryonic antigen levels, and prostate-specific antigen levels were within reference range. A complete blood cell count revealed mild megaloblastic anemia. Subsequent computed tomography of the chest, abdomen, and pelvis revealed an abdominal aortic aneurysm and prostatic enlargement without any evidence of potential malignancies.  Colonoscopy revealed multiple hyperplastic polyps and a tubular adenoma. Cystoscopy was normal, except for evidence of prostate enlargement. Urine cytology was unremarkable. The patient was referred for excision of the lesion with Mohs micrographic surgery. Follow-up was recommended every 3 months for the first 2 years following surgery and every 6 months thereafter to monitor for recurrence or secondary neoplasms.

Figure 1. Intraepidermal proliferation of large cells with abundant clear cytoplasm and large vesicular nuclei distributed throughout the epidermis as individual cells and as variably sized aggregates of cells (H&E, original magnification ×200). (Reference bar indicates 1 mm.) Figure 2. Granular cytoplasm was positive on periodic acid–Schiff staining (original magnification ×200). (Reference bar indicates 1 mm.) Figure 3. Neoplastic Paget cells were characteristically positive on staining for CK7 (original magnification ×200). (Reference bar indicates 1 mm.)

Sir James Paget first described mammary Paget disease of the nipple in 1874 in his report of 15 women with skin eruptions of the nipple and areola and subsequent carcinoma of the underlying breast.¹ Paget also described a patient with a similar eruption on the glans penis and Crocker2 described extramammary Paget disease (EMPD) of the scrotum and penis in 1889. The principle difference between mammary Paget disease and EMPD is the anatomic location.

Extramammary Paget disease is a rare condition that typically affects patients aged 50 to 80 years and is more common in women and white-skinned races.³ Extramammary Paget disease frequently targets cutaneous sites that are rich in apocrine glands. The most commonly affected site is the vulva followed by perineal, perianal, scrotal, and penile skin. Less commonly, the axillae, buttocks, thighs, eyelids, and external auditory canals may be affected.⁴             

Patients with EMPD typically present with well-demarcated, nonresolving, erythematous and eczematous plaques that may have associated crusting, scaling, papillomatous excrescences, lichenification, ulceration, or bleeding. The most common symptom is pruritus, followed by burning, irritation, pain, and tenderness.⁵ Ten percent of patients are asymptomatic. The average interval between symptom onset and diagnosis is 2 years.⁵

Histopathology reveals diffusely infiltrating, irregular, neoplastic Paget cells within the epidermis that are large and vacuolated with abundant pale bluish cytoplasm and large vesicular nuclei, which may be centrally or laterally compressed. The cells may be distributed singly or in groups as strands, nests, or glandular patterns within the lower epidermis, rete ridges, and adnexal structures. Hyperkeratosis, acanthosis, and parakeratosis may also be present. Paget cells stain for immunohistochemical markers of apocrine and eccrine derivation including low-molecular-weight cytokeratins, gross cystic disease fluid protein 15, periodic acid–Schiff stain, and carcinoembryonic antigen.⁵ Perrotto et al⁶ studied 98 specimens from 61 patients and found that CK7 was positive in all EMPD specimens, while CK20 and gross cystic disease fluid protein 15 were positive in large subsets of both primary and secondary EMPD. Cases of EMPD secondary to anorectal adenocarcinoma were largely ERBB2 (formerly HER2/neu) negative and CDX2 positive.⁶

Diagnosis of EMPD should be followed by a thorough investigation for underlying carcinomas. In a review of 197 cases of EMPD, 24% of patients with EMPD had an associated underlying in situ or invasive adnexal apocrine carcinoma, which was associated with a higher mortality rate than in patients without this underlying malignancy. Additionally, 12% of EMPD patients had an associated underlying internal malignancy.⁷ These malignancies may include carcinomas of the urethra, bladder, vagina, cervix, endometrium, prostate, colon, and rectum. Perianal EMPD has a higher frequency of associated malignancies than vulvar EMPD.⁵ The location of EMPD is related to the location of the underlying malignancy; for example, perianal EMPD is associated with colorectal adenocarcinomas, and EMPD of the penis, scrotum, and groin is associated with genitourinary malignancies. Investigations to search for associated malignancies in patients with EMPD may include pelvic ultrasonography and/or magnetic resonance imaging, hysteroscopy, colonoscopy, sigmoidoscopy, cystoscopy, intravenous pyelogram, mammogram, and/or chest radiograph.

The most effective treatment of EMPD is margin-controlled surgical excision. High local recurrence rates may be due to irregular margins, multicentricity, and the tendency of EMPD to involve clinically normal-appearing skin. Hendi et al⁸ noted that EMPD may actually be unifocal with subclinical fingerlike projections extending beyond the main body of the tumor, requiring CK7 immunostaining for visualization to ensure complete margin control. The recurrence rate after standard surgical excision is 33% to 60%. The recurrence rate after excision via Mohs micrographic surgery is 16% for primary EMPD and 50% for recurrent EMPD.⁹ Other treatment modalities include radiotherapy, topical chemotherapy with 5-fluorouracil or imiquimod, and photodynamic therapy.^10-13 Combined systemic chemotherapy with trastuzumab and paclitaxel can be considered for the treatment of ERBB2-positive EMPD.¹⁴

For patients with chronic genital or perianal lesions that are unresponsive to treatment, dermatologists should maintain a high index of suspicion for EMPD. If a patient is diagnosed with EMPD, a full-body skin examination should be performed with palpation of all lymph nodes. Imaging studies directed at the anatomic location of the involved skin should be utilized to search for an underlying internal malignancy.

A 70-year-old man presented with a nonpruritic erythematous scaly plaque in the left suprapubic region of 6 months’ duration that had failed to respond to terbinafine cream 1% after 1 month of treatment of suspected tinea cruris. His medical history was remarkable for hypertension, hyperlipidemia, chronic obstructive pulmonary disease, benign prostatic hyperplasia, an abdominal aortic aneurysm, alcohol dependence, tobacco use disorder, and unintentional weight loss of 15 lb over the last year.

The Diagnosis: Extramammary Paget Disease

A biopsy of the plaque revealed an intraepidermal proliferation of large cells with abundant clear cytoplasm and large vesicular nuclei distributed throughout the epidermis (Figure 1). The neoplastic cells stained positive for both periodic acid–Schiff stain (Figure 2) and CK7 (Figure 3). Chemistry and liver function panel, urine analysis, carcinoembryonic antigen levels, and prostate-specific antigen levels were within reference range. A complete blood cell count revealed mild megaloblastic anemia. Subsequent computed tomography of the chest, abdomen, and pelvis revealed an abdominal aortic aneurysm and prostatic enlargement without any evidence of potential malignancies.  Colonoscopy revealed multiple hyperplastic polyps and a tubular adenoma. Cystoscopy was normal, except for evidence of prostate enlargement. Urine cytology was unremarkable. The patient was referred for excision of the lesion with Mohs micrographic surgery. Follow-up was recommended every 3 months for the first 2 years following surgery and every 6 months thereafter to monitor for recurrence or secondary neoplasms.

Figure 1. Intraepidermal proliferation of large cells with abundant clear cytoplasm and large vesicular nuclei distributed throughout the epidermis as individual cells and as variably sized aggregates of cells (H&E, original magnification ×200). (Reference bar indicates 1 mm.) Figure 2. Granular cytoplasm was positive on periodic acid–Schiff staining (original magnification ×200). (Reference bar indicates 1 mm.) Figure 3. Neoplastic Paget cells were characteristically positive on staining for CK7 (original magnification ×200). (Reference bar indicates 1 mm.)

Sir James Paget first described mammary Paget disease of the nipple in 1874 in his report of 15 women with skin eruptions of the nipple and areola and subsequent carcinoma of the underlying breast.¹ Paget also described a patient with a similar eruption on the glans penis and Crocker2 described extramammary Paget disease (EMPD) of the scrotum and penis in 1889. The principle difference between mammary Paget disease and EMPD is the anatomic location.

Extramammary Paget disease is a rare condition that typically affects patients aged 50 to 80 years and is more common in women and white-skinned races.³ Extramammary Paget disease frequently targets cutaneous sites that are rich in apocrine glands. The most commonly affected site is the vulva followed by perineal, perianal, scrotal, and penile skin. Less commonly, the axillae, buttocks, thighs, eyelids, and external auditory canals may be affected.⁴             

Patients with EMPD typically present with well-demarcated, nonresolving, erythematous and eczematous plaques that may have associated crusting, scaling, papillomatous excrescences, lichenification, ulceration, or bleeding. The most common symptom is pruritus, followed by burning, irritation, pain, and tenderness.⁵ Ten percent of patients are asymptomatic. The average interval between symptom onset and diagnosis is 2 years.⁵

Histopathology reveals diffusely infiltrating, irregular, neoplastic Paget cells within the epidermis that are large and vacuolated with abundant pale bluish cytoplasm and large vesicular nuclei, which may be centrally or laterally compressed. The cells may be distributed singly or in groups as strands, nests, or glandular patterns within the lower epidermis, rete ridges, and adnexal structures. Hyperkeratosis, acanthosis, and parakeratosis may also be present. Paget cells stain for immunohistochemical markers of apocrine and eccrine derivation including low-molecular-weight cytokeratins, gross cystic disease fluid protein 15, periodic acid–Schiff stain, and carcinoembryonic antigen.⁵ Perrotto et al⁶ studied 98 specimens from 61 patients and found that CK7 was positive in all EMPD specimens, while CK20 and gross cystic disease fluid protein 15 were positive in large subsets of both primary and secondary EMPD. Cases of EMPD secondary to anorectal adenocarcinoma were largely ERBB2 (formerly HER2/neu) negative and CDX2 positive.⁶

Diagnosis of EMPD should be followed by a thorough investigation for underlying carcinomas. In a review of 197 cases of EMPD, 24% of patients with EMPD had an associated underlying in situ or invasive adnexal apocrine carcinoma, which was associated with a higher mortality rate than in patients without this underlying malignancy. Additionally, 12% of EMPD patients had an associated underlying internal malignancy.⁷ These malignancies may include carcinomas of the urethra, bladder, vagina, cervix, endometrium, prostate, colon, and rectum. Perianal EMPD has a higher frequency of associated malignancies than vulvar EMPD.⁵ The location of EMPD is related to the location of the underlying malignancy; for example, perianal EMPD is associated with colorectal adenocarcinomas, and EMPD of the penis, scrotum, and groin is associated with genitourinary malignancies. Investigations to search for associated malignancies in patients with EMPD may include pelvic ultrasonography and/or magnetic resonance imaging, hysteroscopy, colonoscopy, sigmoidoscopy, cystoscopy, intravenous pyelogram, mammogram, and/or chest radiograph.

The most effective treatment of EMPD is margin-controlled surgical excision. High local recurrence rates may be due to irregular margins, multicentricity, and the tendency of EMPD to involve clinically normal-appearing skin. Hendi et al⁸ noted that EMPD may actually be unifocal with subclinical fingerlike projections extending beyond the main body of the tumor, requiring CK7 immunostaining for visualization to ensure complete margin control. The recurrence rate after standard surgical excision is 33% to 60%. The recurrence rate after excision via Mohs micrographic surgery is 16% for primary EMPD and 50% for recurrent EMPD.⁹ Other treatment modalities include radiotherapy, topical chemotherapy with 5-fluorouracil or imiquimod, and photodynamic therapy.^10-13 Combined systemic chemotherapy with trastuzumab and paclitaxel can be considered for the treatment of ERBB2-positive EMPD.¹⁴

For patients with chronic genital or perianal lesions that are unresponsive to treatment, dermatologists should maintain a high index of suspicion for EMPD. If a patient is diagnosed with EMPD, a full-body skin examination should be performed with palpation of all lymph nodes. Imaging studies directed at the anatomic location of the involved skin should be utilized to search for an underlying internal malignancy.

A 70-year-old man presented with a nonpruritic erythematous scaly plaque in the left suprapubic region of 6 months’ duration that had failed to respond to terbinafine cream 1% after 1 month of treatment of suspected tinea cruris. His medical history was remarkable for hypertension, hyperlipidemia, chronic obstructive pulmonary disease, benign prostatic hyperplasia, an abdominal aortic aneurysm, alcohol dependence, tobacco use disorder, and unintentional weight loss of 15 lb over the last year.

The Diagnosis: Extramammary Paget Disease

A biopsy of the plaque revealed an intraepidermal proliferation of large cells with abundant clear cytoplasm and large vesicular nuclei distributed throughout the epidermis (Figure 1). The neoplastic cells stained positive for both periodic acid–Schiff stain (Figure 2) and CK7 (Figure 3). Chemistry and liver function panel, urine analysis, carcinoembryonic antigen levels, and prostate-specific antigen levels were within reference range. A complete blood cell count revealed mild megaloblastic anemia. Subsequent computed tomography of the chest, abdomen, and pelvis revealed an abdominal aortic aneurysm and prostatic enlargement without any evidence of potential malignancies.  Colonoscopy revealed multiple hyperplastic polyps and a tubular adenoma. Cystoscopy was normal, except for evidence of prostate enlargement. Urine cytology was unremarkable. The patient was referred for excision of the lesion with Mohs micrographic surgery. Follow-up was recommended every 3 months for the first 2 years following surgery and every 6 months thereafter to monitor for recurrence or secondary neoplasms.

Figure 1. Intraepidermal proliferation of large cells with abundant clear cytoplasm and large vesicular nuclei distributed throughout the epidermis as individual cells and as variably sized aggregates of cells (H&E, original magnification ×200). (Reference bar indicates 1 mm.) Figure 2. Granular cytoplasm was positive on periodic acid–Schiff staining (original magnification ×200). (Reference bar indicates 1 mm.) Figure 3. Neoplastic Paget cells were characteristically positive on staining for CK7 (original magnification ×200). (Reference bar indicates 1 mm.)

Sir James Paget first described mammary Paget disease of the nipple in 1874 in his report of 15 women with skin eruptions of the nipple and areola and subsequent carcinoma of the underlying breast.¹ Paget also described a patient with a similar eruption on the glans penis and Crocker2 described extramammary Paget disease (EMPD) of the scrotum and penis in 1889. The principle difference between mammary Paget disease and EMPD is the anatomic location.

Extramammary Paget disease is a rare condition that typically affects patients aged 50 to 80 years and is more common in women and white-skinned races.³ Extramammary Paget disease frequently targets cutaneous sites that are rich in apocrine glands. The most commonly affected site is the vulva followed by perineal, perianal, scrotal, and penile skin. Less commonly, the axillae, buttocks, thighs, eyelids, and external auditory canals may be affected.⁴             

Patients with EMPD typically present with well-demarcated, nonresolving, erythematous and eczematous plaques that may have associated crusting, scaling, papillomatous excrescences, lichenification, ulceration, or bleeding. The most common symptom is pruritus, followed by burning, irritation, pain, and tenderness.⁵ Ten percent of patients are asymptomatic. The average interval between symptom onset and diagnosis is 2 years.⁵

Histopathology reveals diffusely infiltrating, irregular, neoplastic Paget cells within the epidermis that are large and vacuolated with abundant pale bluish cytoplasm and large vesicular nuclei, which may be centrally or laterally compressed. The cells may be distributed singly or in groups as strands, nests, or glandular patterns within the lower epidermis, rete ridges, and adnexal structures. Hyperkeratosis, acanthosis, and parakeratosis may also be present. Paget cells stain for immunohistochemical markers of apocrine and eccrine derivation including low-molecular-weight cytokeratins, gross cystic disease fluid protein 15, periodic acid–Schiff stain, and carcinoembryonic antigen.⁵ Perrotto et al⁶ studied 98 specimens from 61 patients and found that CK7 was positive in all EMPD specimens, while CK20 and gross cystic disease fluid protein 15 were positive in large subsets of both primary and secondary EMPD. Cases of EMPD secondary to anorectal adenocarcinoma were largely ERBB2 (formerly HER2/neu) negative and CDX2 positive.⁶

Diagnosis of EMPD should be followed by a thorough investigation for underlying carcinomas. In a review of 197 cases of EMPD, 24% of patients with EMPD had an associated underlying in situ or invasive adnexal apocrine carcinoma, which was associated with a higher mortality rate than in patients without this underlying malignancy. Additionally, 12% of EMPD patients had an associated underlying internal malignancy.⁷ These malignancies may include carcinomas of the urethra, bladder, vagina, cervix, endometrium, prostate, colon, and rectum. Perianal EMPD has a higher frequency of associated malignancies than vulvar EMPD.⁵ The location of EMPD is related to the location of the underlying malignancy; for example, perianal EMPD is associated with colorectal adenocarcinomas, and EMPD of the penis, scrotum, and groin is associated with genitourinary malignancies. Investigations to search for associated malignancies in patients with EMPD may include pelvic ultrasonography and/or magnetic resonance imaging, hysteroscopy, colonoscopy, sigmoidoscopy, cystoscopy, intravenous pyelogram, mammogram, and/or chest radiograph.

The most effective treatment of EMPD is margin-controlled surgical excision. High local recurrence rates may be due to irregular margins, multicentricity, and the tendency of EMPD to involve clinically normal-appearing skin. Hendi et al⁸ noted that EMPD may actually be unifocal with subclinical fingerlike projections extending beyond the main body of the tumor, requiring CK7 immunostaining for visualization to ensure complete margin control. The recurrence rate after standard surgical excision is 33% to 60%. The recurrence rate after excision via Mohs micrographic surgery is 16% for primary EMPD and 50% for recurrent EMPD.⁹ Other treatment modalities include radiotherapy, topical chemotherapy with 5-fluorouracil or imiquimod, and photodynamic therapy.^10-13 Combined systemic chemotherapy with trastuzumab and paclitaxel can be considered for the treatment of ERBB2-positive EMPD.¹⁴

For patients with chronic genital or perianal lesions that are unresponsive to treatment, dermatologists should maintain a high index of suspicion for EMPD. If a patient is diagnosed with EMPD, a full-body skin examination should be performed with palpation of all lymph nodes. Imaging studies directed at the anatomic location of the involved skin should be utilized to search for an underlying internal malignancy.

A 19-year-old woman presented with an umbilical mass of 5 months’ duration that had grown in size. Physical examination revealed a 1×1-cm brownish, pedunculated, cauliflower-shaped lesion on the umbilicus. There were no other signs or symptoms of disease. The patient’s personal and family disease history were unremarkable. An excisional biopsy was performed.

The Diagnosis: Acquired Lymphangiectasia

On histopathology numerous dilated channels lined by a single flat layer of endothelial cells were noted within the dermis. The overlying epidermis was papillomatous and acanthotic (Figure 1). The endothelial cells lining the dilated channels were D2-40 positive (Figure 2). Furthermore, the channels contained a pinkish amorphous material and a few red blood cells. The surrounding stroma showed scattered lymphocyte infiltration. These findings were consistent with lymphangiectasia. The lesion has not recurred 4 years following total excision.

Figure 1. Numerous dilated channels lined by flattened, single-layer endothelial cells in the dermis with overlying epidermal papillomatosis and acanthosis (A and B)(H&E, original magnification ×40 and ×200). Figure 2. The flattened, single-layer endothelial cells that lined multiple dilated channels were positive on D2-40 immunochemical staining (original magnifi-cation ×200).

Acquired lymphangiectasia is known by various names, including lymphangioma, acquired lymphangioma, and acquired lymphangioma circumscriptum, which has led to confusion.¹ Acquired lymphangiectasia, which is characterized by dilated superficial lymphatics, develops following damage to previously normal lymphatic channels, leading to a buildup of lymph pressure and backflow.² Acquired lymphangiectasia has been reported as clinically and histologically indistinguishable from lymphangioma circumscriptum²; however, unlike in lymphangiectasia, the suffix -oma denotes a tumor. Our case matched more closely with the typical concept of lymphangiectasia rather than lymphangioma.

Clinical findings of acquired lymphangiectasia usually include translucent, flat or slightly raised, 2- to 5-mm, flesh-colored papules and vesicles.^3,4 Acquired lymphangiectasia has been described with lesions that have verrucous surfaces mimicking warts, condyloma acuminata, or molluscum contagiosum.^5,6 Our case suggests that acquired lymphangiectasia also can present with a pedunculated cauliflowerlike appearance. In general, it develops secondary to certain conditions such as recovery from trauma or surgery, postsurgical fibrosis, and irradiation. Lymphangiectasia often is seen on the arms, axillae, chest wall, and genital area in women and the scrotum, penis, thighs, and pubic region in men, both who have undergone radical surgery and irradiation for treatment of breast and prostate cancer, respectively.³ Our patient did not report any history of trauma to the umbilicus.

On histopathology acquired lymphangiectasia typically shows edematous polypoid nodules with dilated lymphatics. The overlying epidermis usually shows a spectrum of proliferation ranging from mild acanthosis to florid pseudoepitheliomatous hyperplasia with marked hyperkeratosis and parakeratosis. The distinctive finding of lymphangiectasia is the presence of dilated lymphatic spaces within the dermis. The dilated channels are filled with lymphatic fluid and often red and white blood cells. The single layer of flattened endothelial cells generally exhibits immunoreactivity to D2-40 and CD31.¹

Treatment of lymphangiectasia is focused on reducing the pressure within the lymph vessels and managing consequent lymphedema with compression dressings. Simple surgical excision of lesions on sites such as the vulva or legs often is effective.³ If surgical intervention is not an option, cryotherapy, sclerotherapy, cauterization, and treatment with CO₂ lasers also have been utilized with good outcomes.⁷ In the current case, total surgical excision was performed, which provided good results.

A 19-year-old woman presented with an umbilical mass of 5 months’ duration that had grown in size. Physical examination revealed a 1×1-cm brownish, pedunculated, cauliflower-shaped lesion on the umbilicus. There were no other signs or symptoms of disease. The patient’s personal and family disease history were unremarkable. An excisional biopsy was performed.

The Diagnosis: Acquired Lymphangiectasia

On histopathology numerous dilated channels lined by a single flat layer of endothelial cells were noted within the dermis. The overlying epidermis was papillomatous and acanthotic (Figure 1). The endothelial cells lining the dilated channels were D2-40 positive (Figure 2). Furthermore, the channels contained a pinkish amorphous material and a few red blood cells. The surrounding stroma showed scattered lymphocyte infiltration. These findings were consistent with lymphangiectasia. The lesion has not recurred 4 years following total excision.

Figure 1. Numerous dilated channels lined by flattened, single-layer endothelial cells in the dermis with overlying epidermal papillomatosis and acanthosis (A and B)(H&E, original magnification ×40 and ×200). Figure 2. The flattened, single-layer endothelial cells that lined multiple dilated channels were positive on D2-40 immunochemical staining (original magnifi-cation ×200).

Acquired lymphangiectasia is known by various names, including lymphangioma, acquired lymphangioma, and acquired lymphangioma circumscriptum, which has led to confusion.¹ Acquired lymphangiectasia, which is characterized by dilated superficial lymphatics, develops following damage to previously normal lymphatic channels, leading to a buildup of lymph pressure and backflow.² Acquired lymphangiectasia has been reported as clinically and histologically indistinguishable from lymphangioma circumscriptum²; however, unlike in lymphangiectasia, the suffix -oma denotes a tumor. Our case matched more closely with the typical concept of lymphangiectasia rather than lymphangioma.

Clinical findings of acquired lymphangiectasia usually include translucent, flat or slightly raised, 2- to 5-mm, flesh-colored papules and vesicles.^3,4 Acquired lymphangiectasia has been described with lesions that have verrucous surfaces mimicking warts, condyloma acuminata, or molluscum contagiosum.^5,6 Our case suggests that acquired lymphangiectasia also can present with a pedunculated cauliflowerlike appearance. In general, it develops secondary to certain conditions such as recovery from trauma or surgery, postsurgical fibrosis, and irradiation. Lymphangiectasia often is seen on the arms, axillae, chest wall, and genital area in women and the scrotum, penis, thighs, and pubic region in men, both who have undergone radical surgery and irradiation for treatment of breast and prostate cancer, respectively.³ Our patient did not report any history of trauma to the umbilicus.

On histopathology acquired lymphangiectasia typically shows edematous polypoid nodules with dilated lymphatics. The overlying epidermis usually shows a spectrum of proliferation ranging from mild acanthosis to florid pseudoepitheliomatous hyperplasia with marked hyperkeratosis and parakeratosis. The distinctive finding of lymphangiectasia is the presence of dilated lymphatic spaces within the dermis. The dilated channels are filled with lymphatic fluid and often red and white blood cells. The single layer of flattened endothelial cells generally exhibits immunoreactivity to D2-40 and CD31.¹

Treatment of lymphangiectasia is focused on reducing the pressure within the lymph vessels and managing consequent lymphedema with compression dressings. Simple surgical excision of lesions on sites such as the vulva or legs often is effective.³ If surgical intervention is not an option, cryotherapy, sclerotherapy, cauterization, and treatment with CO₂ lasers also have been utilized with good outcomes.⁷ In the current case, total surgical excision was performed, which provided good results.

A 19-year-old woman presented with an umbilical mass of 5 months’ duration that had grown in size. Physical examination revealed a 1×1-cm brownish, pedunculated, cauliflower-shaped lesion on the umbilicus. There were no other signs or symptoms of disease. The patient’s personal and family disease history were unremarkable. An excisional biopsy was performed.

The Diagnosis: Acquired Lymphangiectasia

On histopathology numerous dilated channels lined by a single flat layer of endothelial cells were noted within the dermis. The overlying epidermis was papillomatous and acanthotic (Figure 1). The endothelial cells lining the dilated channels were D2-40 positive (Figure 2). Furthermore, the channels contained a pinkish amorphous material and a few red blood cells. The surrounding stroma showed scattered lymphocyte infiltration. These findings were consistent with lymphangiectasia. The lesion has not recurred 4 years following total excision.

Figure 1. Numerous dilated channels lined by flattened, single-layer endothelial cells in the dermis with overlying epidermal papillomatosis and acanthosis (A and B)(H&E, original magnification ×40 and ×200). Figure 2. The flattened, single-layer endothelial cells that lined multiple dilated channels were positive on D2-40 immunochemical staining (original magnifi-cation ×200).

Acquired lymphangiectasia is known by various names, including lymphangioma, acquired lymphangioma, and acquired lymphangioma circumscriptum, which has led to confusion.¹ Acquired lymphangiectasia, which is characterized by dilated superficial lymphatics, develops following damage to previously normal lymphatic channels, leading to a buildup of lymph pressure and backflow.² Acquired lymphangiectasia has been reported as clinically and histologically indistinguishable from lymphangioma circumscriptum²; however, unlike in lymphangiectasia, the suffix -oma denotes a tumor. Our case matched more closely with the typical concept of lymphangiectasia rather than lymphangioma.

Clinical findings of acquired lymphangiectasia usually include translucent, flat or slightly raised, 2- to 5-mm, flesh-colored papules and vesicles.^3,4 Acquired lymphangiectasia has been described with lesions that have verrucous surfaces mimicking warts, condyloma acuminata, or molluscum contagiosum.^5,6 Our case suggests that acquired lymphangiectasia also can present with a pedunculated cauliflowerlike appearance. In general, it develops secondary to certain conditions such as recovery from trauma or surgery, postsurgical fibrosis, and irradiation. Lymphangiectasia often is seen on the arms, axillae, chest wall, and genital area in women and the scrotum, penis, thighs, and pubic region in men, both who have undergone radical surgery and irradiation for treatment of breast and prostate cancer, respectively.³ Our patient did not report any history of trauma to the umbilicus.

On histopathology acquired lymphangiectasia typically shows edematous polypoid nodules with dilated lymphatics. The overlying epidermis usually shows a spectrum of proliferation ranging from mild acanthosis to florid pseudoepitheliomatous hyperplasia with marked hyperkeratosis and parakeratosis. The distinctive finding of lymphangiectasia is the presence of dilated lymphatic spaces within the dermis. The dilated channels are filled with lymphatic fluid and often red and white blood cells. The single layer of flattened endothelial cells generally exhibits immunoreactivity to D2-40 and CD31.¹

Treatment of lymphangiectasia is focused on reducing the pressure within the lymph vessels and managing consequent lymphedema with compression dressings. Simple surgical excision of lesions on sites such as the vulva or legs often is effective.³ If surgical intervention is not an option, cryotherapy, sclerotherapy, cauterization, and treatment with CO₂ lasers also have been utilized with good outcomes.⁷ In the current case, total surgical excision was performed, which provided good results.

Purpura fulminans is a hematologic emergency, with clinical skin necrosis and laboratory testing showing disseminated intravascular coagulation. The thrombotic occlusion usually affects small and medium-sized blood vessels and may involve any organ. Purpura fulminans has been implicated with sepsis, most commonly meningococcal infections; other infections such as Staphylococcus aureus, groups A and B β-hemolytic streptococci, Streptococcus pneumoniae, and Haemophilus influenzae; and as a sequela to benign childhood infections, such as varicella. Other associations with purpura fulminans include autoimmune disease and heritable or acquired deficiency of anticoagulant proteins, most commonly protein C. We present a rare case of purpura fulminans as the presenting sign of angioimmunoblastic T-cell lymphoma (AITL), an aggressive primary nodal peripheral T-cell lymphoma with a high mortality rate and nonspecific skin manifestations in roughly half of all patients involved.

Case Report

A 56-year-old woman presented with purpuric patches on the left foot (Figure 1A). Seven days after presentation the lesion progressed into ecchymotic geographic plaques and hemorrhagic bullae that spread upward and contralaterally, sparing the digits, trunk, head, neck, and mucous membranes. Ultimately, the involved skin became necrotic and involved 20% of the body surface area (Figure 1B). The lesions were painful with a burning sensation but were not pruritic. The patient also reported intermittent fevers, chills, myalgia, nausea, and shortness of breath. Enlarged lymph nodes were present in the right cervical chain. She denied new medications; stated she had been in good health prior to this episode; and had no history of spontaneous abortion, neurologic symptoms, or other serious illness.

Figure 1. Purpuric patches on the left foot (A). Several days later there were geographic plaques of noninflammatory purpura and ecchymoses with hemorrhagic bullae. There was a sharp demarcation between involved and uninvolved skin (B).

Computed tomography showed prominent diffuse mediastinal, mesenteric, retroperitoneal, and pelvic lymphadenopathy with involvement of the cervical and inguinal areas. Laboratory values showed thrombocytopenia and increased fibrin degradation products. Blood and tissue cultures were negative; the patient also had a negative viral serology, except for Epstein-Barr virus IgG titers (>1:2560). A skin biopsy of the left thigh demonstrated venules and capillaries in the mid and superficial dermis filled with fibrin thrombi without vasculitis (Figure 2). A lymph node biopsy was consistent with a diagnosis of AITL. The lymph node architecture was largely effaced by a polymorphous lymphoid infiltrate that predominantly expanded into paracortical areas and was associated with a prominent arborizing vascular proliferation. The infiltrate was composed of lymphocytes ranging in size from small to medium, with ample cytoplasm, coarsely clumped chromatin, and mildly irregular nuclear membranes. Large atypical lymphocytes with features of immunoblasts were easily identified. An associated inflammatory background composed of eosinophils, plasma cells, and histiocytes was present (Figure 3). The atypical lymphocytes stained positive for CD3and CD10 on immunohistochemistry. Additionally, a subset of large immunoblastlike lymphocytes was positive for Epstein-Barr–encoded small RNAs by in situ hybridization.

Figure 2. Fibrin thrombi filled the lumen of small arteries, arterioles, and capillaries. Red blood cell extravasation with paucicellular subepidermal bulla overlying a degenerative dermis also was seen (A)(H&E, original magnification ×100). A noninflammatory fibrin thrombus occluded a mid dermal vessel (B)(H&E, original magni-fication ×400).

The patient was started on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. She received 2 cycles with positive response based on subsequent computed tomography and positron emission tomography scans that showed regression of her disease as well as the lack of formation of new skin lesions. She was transferred to a burn unit where she had continuing treatment and skin grafts. Despite 2 cycles of chemotherapy, broad-spectrum antibiotics, and daily wound care management, the patient died secondary to sepsis 6 months after presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a primary nodal lymphoma with occasional cutaneous involvement. Cutaneous manifestations occur in roughly half of all patients with AITL¹ and have mainly been described as erythematous macules and papules that can resemble a viral exanthem or a drug reaction.² However, other skin manifestations include urticaria, papulovesicular lesions, nodules, erythroderma,³ and to a lesser degree purpura.⁴ The lesions have been noted to occur prior to, concurrent with, or anytime during the disease.^3,5,6 This aggressive lymphoma has mortality rates ranging from 50% to 72%, and median survival ranges from 11 to 30 months.⁶

Figure 3. A high-power photomicrograph showed lymphoid cells admixed with immunoblasts (black arrowhead) and plasma cells. Vascular proliferation (red arrowhead) also was noted (H&E, original magnifi-cation ×400).

To arrive at the correct diagnosis of AITL, a nodal biopsy with immunochemistry is necessary. Classic findings on histopathology include effacement of normal architecture, marked vascular proliferation, and aggregates of atypical lymphoid cells. CD10 has been shown to be a good objective criterion for the diagnosis of AITL,4 with characteristic tumor cells expressing CD10. Nodal Epstein-Barr virus–positive lymphocytes often are present.² Other T-cell lymphomas with primarily nodal presentation along with peripheral T-cell lymphoma include peripheral T-cell lymphoma unspecified type and anaplastic large cell lymphoma, according to the World Health Organization classification.7 Anaplastic large cell lymphoma is easily distinguished from AITL based on histopathology, immunostaining, and clinical presentation. Until recently, peripheral T-cell lymphoma unspecified type and reactive lymphoid hyperplasia presented a challenge to differentiate from AITL, especially in the early phases of the disease; however, the introduction of CD10 as a phenotypic marker has been instrumental in distinguishing AITL from other T-cell lymphomas with primary nodal involvement.^1,4

The development of purpura fulminans and disseminated intravascular coagulation in a patient with AITL is rare. Although the exact mechanism for the thrombus formation in the skin has not been elucidated, purpura fulminans typically develops secondary to a severe infection. The exact incidence of purpura fulminans in the setting of AITL is unknown, but purpura as a cutaneous eruption has been associated as a clinical finding in AITL.⁶ Although our case may be a rare presentation of AITL, a prompt and accurate diagnosis can drastically change the prognosis of this aggressive disease.

Purpura fulminans is a hematologic emergency, with clinical skin necrosis and laboratory testing showing disseminated intravascular coagulation. The thrombotic occlusion usually affects small and medium-sized blood vessels and may involve any organ. Purpura fulminans has been implicated with sepsis, most commonly meningococcal infections; other infections such as Staphylococcus aureus, groups A and B β-hemolytic streptococci, Streptococcus pneumoniae, and Haemophilus influenzae; and as a sequela to benign childhood infections, such as varicella. Other associations with purpura fulminans include autoimmune disease and heritable or acquired deficiency of anticoagulant proteins, most commonly protein C. We present a rare case of purpura fulminans as the presenting sign of angioimmunoblastic T-cell lymphoma (AITL), an aggressive primary nodal peripheral T-cell lymphoma with a high mortality rate and nonspecific skin manifestations in roughly half of all patients involved.

Case Report

A 56-year-old woman presented with purpuric patches on the left foot (Figure 1A). Seven days after presentation the lesion progressed into ecchymotic geographic plaques and hemorrhagic bullae that spread upward and contralaterally, sparing the digits, trunk, head, neck, and mucous membranes. Ultimately, the involved skin became necrotic and involved 20% of the body surface area (Figure 1B). The lesions were painful with a burning sensation but were not pruritic. The patient also reported intermittent fevers, chills, myalgia, nausea, and shortness of breath. Enlarged lymph nodes were present in the right cervical chain. She denied new medications; stated she had been in good health prior to this episode; and had no history of spontaneous abortion, neurologic symptoms, or other serious illness.

Figure 1. Purpuric patches on the left foot (A). Several days later there were geographic plaques of noninflammatory purpura and ecchymoses with hemorrhagic bullae. There was a sharp demarcation between involved and uninvolved skin (B).

Computed tomography showed prominent diffuse mediastinal, mesenteric, retroperitoneal, and pelvic lymphadenopathy with involvement of the cervical and inguinal areas. Laboratory values showed thrombocytopenia and increased fibrin degradation products. Blood and tissue cultures were negative; the patient also had a negative viral serology, except for Epstein-Barr virus IgG titers (>1:2560). A skin biopsy of the left thigh demonstrated venules and capillaries in the mid and superficial dermis filled with fibrin thrombi without vasculitis (Figure 2). A lymph node biopsy was consistent with a diagnosis of AITL. The lymph node architecture was largely effaced by a polymorphous lymphoid infiltrate that predominantly expanded into paracortical areas and was associated with a prominent arborizing vascular proliferation. The infiltrate was composed of lymphocytes ranging in size from small to medium, with ample cytoplasm, coarsely clumped chromatin, and mildly irregular nuclear membranes. Large atypical lymphocytes with features of immunoblasts were easily identified. An associated inflammatory background composed of eosinophils, plasma cells, and histiocytes was present (Figure 3). The atypical lymphocytes stained positive for CD3and CD10 on immunohistochemistry. Additionally, a subset of large immunoblastlike lymphocytes was positive for Epstein-Barr–encoded small RNAs by in situ hybridization.

Figure 2. Fibrin thrombi filled the lumen of small arteries, arterioles, and capillaries. Red blood cell extravasation with paucicellular subepidermal bulla overlying a degenerative dermis also was seen (A)(H&E, original magnification ×100). A noninflammatory fibrin thrombus occluded a mid dermal vessel (B)(H&E, original magni-fication ×400).

The patient was started on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. She received 2 cycles with positive response based on subsequent computed tomography and positron emission tomography scans that showed regression of her disease as well as the lack of formation of new skin lesions. She was transferred to a burn unit where she had continuing treatment and skin grafts. Despite 2 cycles of chemotherapy, broad-spectrum antibiotics, and daily wound care management, the patient died secondary to sepsis 6 months after presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a primary nodal lymphoma with occasional cutaneous involvement. Cutaneous manifestations occur in roughly half of all patients with AITL¹ and have mainly been described as erythematous macules and papules that can resemble a viral exanthem or a drug reaction.² However, other skin manifestations include urticaria, papulovesicular lesions, nodules, erythroderma,³ and to a lesser degree purpura.⁴ The lesions have been noted to occur prior to, concurrent with, or anytime during the disease.^3,5,6 This aggressive lymphoma has mortality rates ranging from 50% to 72%, and median survival ranges from 11 to 30 months.⁶

Figure 3. A high-power photomicrograph showed lymphoid cells admixed with immunoblasts (black arrowhead) and plasma cells. Vascular proliferation (red arrowhead) also was noted (H&E, original magnifi-cation ×400).

To arrive at the correct diagnosis of AITL, a nodal biopsy with immunochemistry is necessary. Classic findings on histopathology include effacement of normal architecture, marked vascular proliferation, and aggregates of atypical lymphoid cells. CD10 has been shown to be a good objective criterion for the diagnosis of AITL,4 with characteristic tumor cells expressing CD10. Nodal Epstein-Barr virus–positive lymphocytes often are present.² Other T-cell lymphomas with primarily nodal presentation along with peripheral T-cell lymphoma include peripheral T-cell lymphoma unspecified type and anaplastic large cell lymphoma, according to the World Health Organization classification.7 Anaplastic large cell lymphoma is easily distinguished from AITL based on histopathology, immunostaining, and clinical presentation. Until recently, peripheral T-cell lymphoma unspecified type and reactive lymphoid hyperplasia presented a challenge to differentiate from AITL, especially in the early phases of the disease; however, the introduction of CD10 as a phenotypic marker has been instrumental in distinguishing AITL from other T-cell lymphomas with primary nodal involvement.^1,4

The development of purpura fulminans and disseminated intravascular coagulation in a patient with AITL is rare. Although the exact mechanism for the thrombus formation in the skin has not been elucidated, purpura fulminans typically develops secondary to a severe infection. The exact incidence of purpura fulminans in the setting of AITL is unknown, but purpura as a cutaneous eruption has been associated as a clinical finding in AITL.⁶ Although our case may be a rare presentation of AITL, a prompt and accurate diagnosis can drastically change the prognosis of this aggressive disease.

Purpura fulminans is a hematologic emergency, with clinical skin necrosis and laboratory testing showing disseminated intravascular coagulation. The thrombotic occlusion usually affects small and medium-sized blood vessels and may involve any organ. Purpura fulminans has been implicated with sepsis, most commonly meningococcal infections; other infections such as Staphylococcus aureus, groups A and B β-hemolytic streptococci, Streptococcus pneumoniae, and Haemophilus influenzae; and as a sequela to benign childhood infections, such as varicella. Other associations with purpura fulminans include autoimmune disease and heritable or acquired deficiency of anticoagulant proteins, most commonly protein C. We present a rare case of purpura fulminans as the presenting sign of angioimmunoblastic T-cell lymphoma (AITL), an aggressive primary nodal peripheral T-cell lymphoma with a high mortality rate and nonspecific skin manifestations in roughly half of all patients involved.

Case Report

A 56-year-old woman presented with purpuric patches on the left foot (Figure 1A). Seven days after presentation the lesion progressed into ecchymotic geographic plaques and hemorrhagic bullae that spread upward and contralaterally, sparing the digits, trunk, head, neck, and mucous membranes. Ultimately, the involved skin became necrotic and involved 20% of the body surface area (Figure 1B). The lesions were painful with a burning sensation but were not pruritic. The patient also reported intermittent fevers, chills, myalgia, nausea, and shortness of breath. Enlarged lymph nodes were present in the right cervical chain. She denied new medications; stated she had been in good health prior to this episode; and had no history of spontaneous abortion, neurologic symptoms, or other serious illness.

Figure 1. Purpuric patches on the left foot (A). Several days later there were geographic plaques of noninflammatory purpura and ecchymoses with hemorrhagic bullae. There was a sharp demarcation between involved and uninvolved skin (B).

Computed tomography showed prominent diffuse mediastinal, mesenteric, retroperitoneal, and pelvic lymphadenopathy with involvement of the cervical and inguinal areas. Laboratory values showed thrombocytopenia and increased fibrin degradation products. Blood and tissue cultures were negative; the patient also had a negative viral serology, except for Epstein-Barr virus IgG titers (>1:2560). A skin biopsy of the left thigh demonstrated venules and capillaries in the mid and superficial dermis filled with fibrin thrombi without vasculitis (Figure 2). A lymph node biopsy was consistent with a diagnosis of AITL. The lymph node architecture was largely effaced by a polymorphous lymphoid infiltrate that predominantly expanded into paracortical areas and was associated with a prominent arborizing vascular proliferation. The infiltrate was composed of lymphocytes ranging in size from small to medium, with ample cytoplasm, coarsely clumped chromatin, and mildly irregular nuclear membranes. Large atypical lymphocytes with features of immunoblasts were easily identified. An associated inflammatory background composed of eosinophils, plasma cells, and histiocytes was present (Figure 3). The atypical lymphocytes stained positive for CD3and CD10 on immunohistochemistry. Additionally, a subset of large immunoblastlike lymphocytes was positive for Epstein-Barr–encoded small RNAs by in situ hybridization.

Figure 2. Fibrin thrombi filled the lumen of small arteries, arterioles, and capillaries. Red blood cell extravasation with paucicellular subepidermal bulla overlying a degenerative dermis also was seen (A)(H&E, original magnification ×100). A noninflammatory fibrin thrombus occluded a mid dermal vessel (B)(H&E, original magni-fication ×400).

The patient was started on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. She received 2 cycles with positive response based on subsequent computed tomography and positron emission tomography scans that showed regression of her disease as well as the lack of formation of new skin lesions. She was transferred to a burn unit where she had continuing treatment and skin grafts. Despite 2 cycles of chemotherapy, broad-spectrum antibiotics, and daily wound care management, the patient died secondary to sepsis 6 months after presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a primary nodal lymphoma with occasional cutaneous involvement. Cutaneous manifestations occur in roughly half of all patients with AITL¹ and have mainly been described as erythematous macules and papules that can resemble a viral exanthem or a drug reaction.² However, other skin manifestations include urticaria, papulovesicular lesions, nodules, erythroderma,³ and to a lesser degree purpura.⁴ The lesions have been noted to occur prior to, concurrent with, or anytime during the disease.^3,5,6 This aggressive lymphoma has mortality rates ranging from 50% to 72%, and median survival ranges from 11 to 30 months.⁶

Figure 3. A high-power photomicrograph showed lymphoid cells admixed with immunoblasts (black arrowhead) and plasma cells. Vascular proliferation (red arrowhead) also was noted (H&E, original magnifi-cation ×400).

To arrive at the correct diagnosis of AITL, a nodal biopsy with immunochemistry is necessary. Classic findings on histopathology include effacement of normal architecture, marked vascular proliferation, and aggregates of atypical lymphoid cells. CD10 has been shown to be a good objective criterion for the diagnosis of AITL,4 with characteristic tumor cells expressing CD10. Nodal Epstein-Barr virus–positive lymphocytes often are present.² Other T-cell lymphomas with primarily nodal presentation along with peripheral T-cell lymphoma include peripheral T-cell lymphoma unspecified type and anaplastic large cell lymphoma, according to the World Health Organization classification.7 Anaplastic large cell lymphoma is easily distinguished from AITL based on histopathology, immunostaining, and clinical presentation. Until recently, peripheral T-cell lymphoma unspecified type and reactive lymphoid hyperplasia presented a challenge to differentiate from AITL, especially in the early phases of the disease; however, the introduction of CD10 as a phenotypic marker has been instrumental in distinguishing AITL from other T-cell lymphomas with primary nodal involvement.^1,4

The development of purpura fulminans and disseminated intravascular coagulation in a patient with AITL is rare. Although the exact mechanism for the thrombus formation in the skin has not been elucidated, purpura fulminans typically develops secondary to a severe infection. The exact incidence of purpura fulminans in the setting of AITL is unknown, but purpura as a cutaneous eruption has been associated as a clinical finding in AITL.⁶ Although our case may be a rare presentation of AITL, a prompt and accurate diagnosis can drastically change the prognosis of this aggressive disease.

Epithelioid sarcoma (ES) is a rare malignant soft tissue neoplasm that is most often encountered on the distal extremities of young adults.¹ Epithelioid sarcoma is notorious for its tendency to mimic palisading granulomatous processes such as granuloma annulare. We report a case of ES on the right hand of a 23-year-old man that resembled a benign fibrous histiocytoma (dermatofibroma) on incisional biopsy. The typical histopathologic features of ES were identified after amputation of the hand and evaluation of the deeper regions of the tumor. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.

Figure 1. A 0.8×0.6-cm ulcerated nodule on the hypothenar region of the right hand (A). Four months after initial presentation the nodule measured 1.4×1 cm (B).

Case Report

A 23-year-old man presented with a nonhealing lesion on the right palm. His medical history was remarkable for a giant cell tumor of the tendon sheath involving the right fifth finger that had been treated via excision at an outside institution 2 years prior. Clinical examination revealed a 0.8×0.6-cm painful, firm, ulcerated dermal nodule with a hemorrhagic crust on the palmar surface of the right hand (Figure 1A). The clinical differential diagnosis included melanoma, traumatized verruca vulgaris, thrombosed pyogenic granuloma, and foreign body. A shave biopsy demonstrated verrucous epidermal hyperplasia, but the specimen did not include the dermis. Cultures of the lesion were positive for Staphylococcus aureus, and antibiotic therapy was initiated. In light of the clinical findings and the patient’s history of a giant cell tumor, imaging studies were performed. Magnetic resonance angiography showed abnormal masslike infiltrative enhancement throughout the soft tissues surrounding the right fifth metacarpal bone. The differential included a recurrent giant cell tumor, fibromatosis, and other soft tissue neoplasms.

After several missed appointments and surgery cancellations, the patient returned 4 months later for an incisional biopsy. Physical examination revealed a persistent palmar ulcer that had grown to 1.4×1 cm in size, along with an indurated purple plaque wrapping around the ulnar aspect of the right hand (Figure 1B). The biopsy demonstrated a proliferation of spindled and ovoid cells with scant cytoplasm that surrounded sclerotic collagen bundles resembling a dermatofibroma (Figure 2A). Cytologic atypia and mitotic activity were absent (Figure 2B). Glass slides of the original biopsy, which ultimately led to the diagnosis of the giant cell tumor of the tendon sheath more than 2 years earlier, were obtained and showed similar features. The proliferating cells were strongly and diffusely immunoreactive for vimentin, CD34, and cancer antigen 125 (CA 125). Scattered tumor cells strongly expressed cytokeratins (CKs) AE1/AE3 and cell adhesion molecule 5.2 (Figure 3). Staining for CD99 and epithelial membrane antigen was diffuse but weak. Factor XIIIa, S-100, CK7, smooth muscle actin, muscle-specific actin (HHF35), CD31, CD68, and B-cell lymphoma 2 were negative within the proliferating cells. Based on the clinical examination and results of the immunohistochemical staining, a diagnosis of ES was favored.

Figure 2. Low-power view of an incisional biopsy resembled a fibrohistiocytomalike neoplasm, as the tumor was composed of plump spindle cells that trapped sclerotic collagen bundles (A)(H&E, original magnification ×40). The tumor lacked significant cytologic atypia and mitotic figures were not seen (B)(H&E, original magnification ×200).

After a negative metastatic workup, amputation of the right hand was performed. The amputation specimen showed a tumor that extended through the entire hand with encasement of large vessels and tendons. Although the more superficial regions were cytologically bland, deep-seated regions of the tumor exhibited greater cellularity, nuclear pleomorphism, and mitotic activity (Figure 4). There was no bone involvement. Right axillary sentinel lymph nodes were negative for metastasis. Eighteen months later the patient developed chest and back pain with dyspnea. Thorascopic surgery was performed for a left pleural effusion and metastases to the left parietal pleura and adjacent soft tissue were identified. The patient was subsequently lost to follow-up.

Comment

First described by Enzinger¹ in 1970, ES is a rare malignant soft tissue neoplasm that most frequently arises on the hands, forearms, and pretibial soft tissues of young adults.^1-3 It is an aggressive tumor characterized by frequent recurrences and a high metastatic rate, with lung and regional lymph nodes being favored metastatic sites.^1-5 Periods of several months or even years often pass between the initial presentation and establishment of a correct diagnosis, as ES frequently is mistaken for other benign conditions. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.^6,7 In his original series of 62 cases, Enzinger¹ noted that 17 patients were referred for treatment with a diagnosis of a benign fibrohistiocytic neoplasm, and other reports have described a resemblance to fibrous and fibrohistiocytic neoplasms.^8-11 Mirra et al¹⁰ designated these tumors as fibromalike variants of ES. Additional subtypes of ES have subsequently been recognized, including those described as angiomatoid or angiosarcomalike, reflecting the potential of ES to resemble vascular tumors.¹² A proximal type of ES also has been described. This lesion presents as a deep-seated tumor on the proximal limbs and is associated with more aggressive behavior. It lacks the granulomalike pattern and has more prominent epithelioid and rhabdoid histological presentation.^13-15

Epithelioid sarcoma is a mesenchymal tumor that can display multidirectional differentiation that is primarily epithelial.¹⁶ The precise histogenesis of ES remains unclear, but studies have demonstrated a spectrum of differentiation that ranges from primitive myofibroblast or fibrohistiocytelike cells to those with well-developed epithelial properties.^16,17 Epithelioid sarcoma characteristically coexpresses vimentin and low-molecular-weight CKs such as cell adhesion molecule 5.2. The tumor cells often are immunoreactive for epithelial membrane antigen and more than 50% of cases exhibit remarkable CD34 positivity.¹⁶ More recent studies have further refined the immunophenotype, demonstrating frequent expression of CK8 and CK19 but less commonly CK7, CK20, CK34bE12, and CK5/6.^18-20 Additional studies reported that in 10 of 11 cases, ES was positive for CA 125 on immunohistochemical staining, and 3 of 5 patients also had elevated serum CA 125 levels.^21,22 More recently, Hoshino et al²³ showed elevated serum CA 125 levels in 5 of 7 patients with ES. Cancer antigen 125 is a high-molecular-weight glycoprotein commonly used in the identification of epithelial ovarian carcinomas; however, it also has been described in a number of other neoplasms including carcinomas of the breast, lungs, and colon and lymphoma.^24-27 Although it appears that the addition of CA 125 to a panel of other immunohistochemical stains may be helpful in differentiating ES from other soft tissue sarcomas and serum CA 125 levels may help determine tumor burden, currently the number of cases studied is too small to definitively make that conclusion.^21,23 In our case, the tumor cells were strongly and diffusely positive for CA 125. Serum CA 125 levels were not available.

Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).

Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&E, original magnification ×400).

Cytogenetic studies have failed to identify a consistent chromosomal abnormality in ES.⁵ Some analyses performed by comparative genomic hybridization on isolated cases and small case series indicate that the most frequent alterations involve 8q, 18q11, and 22q11.^13,28,29 The tumor suppressor gene SMARCB1/INI1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1/integrase interactor 1) has been mapped to 22q11, and ES commonly shows absence of nuclear staining for this protein, indicating inactivation.^13-15

Conclusion

Benign fibrohistiocytic proliferations should be included in the differential of histological mimickers of ES. Deep biopsies are essential to differentiate these benign tumors from fibrous histiocytomalike or fibromalike lesions of ES because superficial portions of ES may be well differentiated.

Epithelioid sarcoma (ES) is a rare malignant soft tissue neoplasm that is most often encountered on the distal extremities of young adults.¹ Epithelioid sarcoma is notorious for its tendency to mimic palisading granulomatous processes such as granuloma annulare. We report a case of ES on the right hand of a 23-year-old man that resembled a benign fibrous histiocytoma (dermatofibroma) on incisional biopsy. The typical histopathologic features of ES were identified after amputation of the hand and evaluation of the deeper regions of the tumor. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.

Figure 1. A 0.8×0.6-cm ulcerated nodule on the hypothenar region of the right hand (A). Four months after initial presentation the nodule measured 1.4×1 cm (B).

Case Report

A 23-year-old man presented with a nonhealing lesion on the right palm. His medical history was remarkable for a giant cell tumor of the tendon sheath involving the right fifth finger that had been treated via excision at an outside institution 2 years prior. Clinical examination revealed a 0.8×0.6-cm painful, firm, ulcerated dermal nodule with a hemorrhagic crust on the palmar surface of the right hand (Figure 1A). The clinical differential diagnosis included melanoma, traumatized verruca vulgaris, thrombosed pyogenic granuloma, and foreign body. A shave biopsy demonstrated verrucous epidermal hyperplasia, but the specimen did not include the dermis. Cultures of the lesion were positive for Staphylococcus aureus, and antibiotic therapy was initiated. In light of the clinical findings and the patient’s history of a giant cell tumor, imaging studies were performed. Magnetic resonance angiography showed abnormal masslike infiltrative enhancement throughout the soft tissues surrounding the right fifth metacarpal bone. The differential included a recurrent giant cell tumor, fibromatosis, and other soft tissue neoplasms.

After several missed appointments and surgery cancellations, the patient returned 4 months later for an incisional biopsy. Physical examination revealed a persistent palmar ulcer that had grown to 1.4×1 cm in size, along with an indurated purple plaque wrapping around the ulnar aspect of the right hand (Figure 1B). The biopsy demonstrated a proliferation of spindled and ovoid cells with scant cytoplasm that surrounded sclerotic collagen bundles resembling a dermatofibroma (Figure 2A). Cytologic atypia and mitotic activity were absent (Figure 2B). Glass slides of the original biopsy, which ultimately led to the diagnosis of the giant cell tumor of the tendon sheath more than 2 years earlier, were obtained and showed similar features. The proliferating cells were strongly and diffusely immunoreactive for vimentin, CD34, and cancer antigen 125 (CA 125). Scattered tumor cells strongly expressed cytokeratins (CKs) AE1/AE3 and cell adhesion molecule 5.2 (Figure 3). Staining for CD99 and epithelial membrane antigen was diffuse but weak. Factor XIIIa, S-100, CK7, smooth muscle actin, muscle-specific actin (HHF35), CD31, CD68, and B-cell lymphoma 2 were negative within the proliferating cells. Based on the clinical examination and results of the immunohistochemical staining, a diagnosis of ES was favored.

Figure 2. Low-power view of an incisional biopsy resembled a fibrohistiocytomalike neoplasm, as the tumor was composed of plump spindle cells that trapped sclerotic collagen bundles (A)(H&E, original magnification ×40). The tumor lacked significant cytologic atypia and mitotic figures were not seen (B)(H&E, original magnification ×200).

After a negative metastatic workup, amputation of the right hand was performed. The amputation specimen showed a tumor that extended through the entire hand with encasement of large vessels and tendons. Although the more superficial regions were cytologically bland, deep-seated regions of the tumor exhibited greater cellularity, nuclear pleomorphism, and mitotic activity (Figure 4). There was no bone involvement. Right axillary sentinel lymph nodes were negative for metastasis. Eighteen months later the patient developed chest and back pain with dyspnea. Thorascopic surgery was performed for a left pleural effusion and metastases to the left parietal pleura and adjacent soft tissue were identified. The patient was subsequently lost to follow-up.

Comment

First described by Enzinger¹ in 1970, ES is a rare malignant soft tissue neoplasm that most frequently arises on the hands, forearms, and pretibial soft tissues of young adults.^1-3 It is an aggressive tumor characterized by frequent recurrences and a high metastatic rate, with lung and regional lymph nodes being favored metastatic sites.^1-5 Periods of several months or even years often pass between the initial presentation and establishment of a correct diagnosis, as ES frequently is mistaken for other benign conditions. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.^6,7 In his original series of 62 cases, Enzinger¹ noted that 17 patients were referred for treatment with a diagnosis of a benign fibrohistiocytic neoplasm, and other reports have described a resemblance to fibrous and fibrohistiocytic neoplasms.^8-11 Mirra et al¹⁰ designated these tumors as fibromalike variants of ES. Additional subtypes of ES have subsequently been recognized, including those described as angiomatoid or angiosarcomalike, reflecting the potential of ES to resemble vascular tumors.¹² A proximal type of ES also has been described. This lesion presents as a deep-seated tumor on the proximal limbs and is associated with more aggressive behavior. It lacks the granulomalike pattern and has more prominent epithelioid and rhabdoid histological presentation.^13-15

Epithelioid sarcoma is a mesenchymal tumor that can display multidirectional differentiation that is primarily epithelial.¹⁶ The precise histogenesis of ES remains unclear, but studies have demonstrated a spectrum of differentiation that ranges from primitive myofibroblast or fibrohistiocytelike cells to those with well-developed epithelial properties.^16,17 Epithelioid sarcoma characteristically coexpresses vimentin and low-molecular-weight CKs such as cell adhesion molecule 5.2. The tumor cells often are immunoreactive for epithelial membrane antigen and more than 50% of cases exhibit remarkable CD34 positivity.¹⁶ More recent studies have further refined the immunophenotype, demonstrating frequent expression of CK8 and CK19 but less commonly CK7, CK20, CK34bE12, and CK5/6.^18-20 Additional studies reported that in 10 of 11 cases, ES was positive for CA 125 on immunohistochemical staining, and 3 of 5 patients also had elevated serum CA 125 levels.^21,22 More recently, Hoshino et al²³ showed elevated serum CA 125 levels in 5 of 7 patients with ES. Cancer antigen 125 is a high-molecular-weight glycoprotein commonly used in the identification of epithelial ovarian carcinomas; however, it also has been described in a number of other neoplasms including carcinomas of the breast, lungs, and colon and lymphoma.^24-27 Although it appears that the addition of CA 125 to a panel of other immunohistochemical stains may be helpful in differentiating ES from other soft tissue sarcomas and serum CA 125 levels may help determine tumor burden, currently the number of cases studied is too small to definitively make that conclusion.^21,23 In our case, the tumor cells were strongly and diffusely positive for CA 125. Serum CA 125 levels were not available.

Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).

Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&E, original magnification ×400).

Cytogenetic studies have failed to identify a consistent chromosomal abnormality in ES.⁵ Some analyses performed by comparative genomic hybridization on isolated cases and small case series indicate that the most frequent alterations involve 8q, 18q11, and 22q11.^13,28,29 The tumor suppressor gene SMARCB1/INI1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1/integrase interactor 1) has been mapped to 22q11, and ES commonly shows absence of nuclear staining for this protein, indicating inactivation.^13-15

Conclusion

Benign fibrohistiocytic proliferations should be included in the differential of histological mimickers of ES. Deep biopsies are essential to differentiate these benign tumors from fibrous histiocytomalike or fibromalike lesions of ES because superficial portions of ES may be well differentiated.

Epithelioid sarcoma (ES) is a rare malignant soft tissue neoplasm that is most often encountered on the distal extremities of young adults.¹ Epithelioid sarcoma is notorious for its tendency to mimic palisading granulomatous processes such as granuloma annulare. We report a case of ES on the right hand of a 23-year-old man that resembled a benign fibrous histiocytoma (dermatofibroma) on incisional biopsy. The typical histopathologic features of ES were identified after amputation of the hand and evaluation of the deeper regions of the tumor. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.

Figure 1. A 0.8×0.6-cm ulcerated nodule on the hypothenar region of the right hand (A). Four months after initial presentation the nodule measured 1.4×1 cm (B).

Case Report

A 23-year-old man presented with a nonhealing lesion on the right palm. His medical history was remarkable for a giant cell tumor of the tendon sheath involving the right fifth finger that had been treated via excision at an outside institution 2 years prior. Clinical examination revealed a 0.8×0.6-cm painful, firm, ulcerated dermal nodule with a hemorrhagic crust on the palmar surface of the right hand (Figure 1A). The clinical differential diagnosis included melanoma, traumatized verruca vulgaris, thrombosed pyogenic granuloma, and foreign body. A shave biopsy demonstrated verrucous epidermal hyperplasia, but the specimen did not include the dermis. Cultures of the lesion were positive for Staphylococcus aureus, and antibiotic therapy was initiated. In light of the clinical findings and the patient’s history of a giant cell tumor, imaging studies were performed. Magnetic resonance angiography showed abnormal masslike infiltrative enhancement throughout the soft tissues surrounding the right fifth metacarpal bone. The differential included a recurrent giant cell tumor, fibromatosis, and other soft tissue neoplasms.

After several missed appointments and surgery cancellations, the patient returned 4 months later for an incisional biopsy. Physical examination revealed a persistent palmar ulcer that had grown to 1.4×1 cm in size, along with an indurated purple plaque wrapping around the ulnar aspect of the right hand (Figure 1B). The biopsy demonstrated a proliferation of spindled and ovoid cells with scant cytoplasm that surrounded sclerotic collagen bundles resembling a dermatofibroma (Figure 2A). Cytologic atypia and mitotic activity were absent (Figure 2B). Glass slides of the original biopsy, which ultimately led to the diagnosis of the giant cell tumor of the tendon sheath more than 2 years earlier, were obtained and showed similar features. The proliferating cells were strongly and diffusely immunoreactive for vimentin, CD34, and cancer antigen 125 (CA 125). Scattered tumor cells strongly expressed cytokeratins (CKs) AE1/AE3 and cell adhesion molecule 5.2 (Figure 3). Staining for CD99 and epithelial membrane antigen was diffuse but weak. Factor XIIIa, S-100, CK7, smooth muscle actin, muscle-specific actin (HHF35), CD31, CD68, and B-cell lymphoma 2 were negative within the proliferating cells. Based on the clinical examination and results of the immunohistochemical staining, a diagnosis of ES was favored.

Figure 2. Low-power view of an incisional biopsy resembled a fibrohistiocytomalike neoplasm, as the tumor was composed of plump spindle cells that trapped sclerotic collagen bundles (A)(H&E, original magnification ×40). The tumor lacked significant cytologic atypia and mitotic figures were not seen (B)(H&E, original magnification ×200).

After a negative metastatic workup, amputation of the right hand was performed. The amputation specimen showed a tumor that extended through the entire hand with encasement of large vessels and tendons. Although the more superficial regions were cytologically bland, deep-seated regions of the tumor exhibited greater cellularity, nuclear pleomorphism, and mitotic activity (Figure 4). There was no bone involvement. Right axillary sentinel lymph nodes were negative for metastasis. Eighteen months later the patient developed chest and back pain with dyspnea. Thorascopic surgery was performed for a left pleural effusion and metastases to the left parietal pleura and adjacent soft tissue were identified. The patient was subsequently lost to follow-up.

Comment

First described by Enzinger¹ in 1970, ES is a rare malignant soft tissue neoplasm that most frequently arises on the hands, forearms, and pretibial soft tissues of young adults.^1-3 It is an aggressive tumor characterized by frequent recurrences and a high metastatic rate, with lung and regional lymph nodes being favored metastatic sites.^1-5 Periods of several months or even years often pass between the initial presentation and establishment of a correct diagnosis, as ES frequently is mistaken for other benign conditions. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.^6,7 In his original series of 62 cases, Enzinger¹ noted that 17 patients were referred for treatment with a diagnosis of a benign fibrohistiocytic neoplasm, and other reports have described a resemblance to fibrous and fibrohistiocytic neoplasms.^8-11 Mirra et al¹⁰ designated these tumors as fibromalike variants of ES. Additional subtypes of ES have subsequently been recognized, including those described as angiomatoid or angiosarcomalike, reflecting the potential of ES to resemble vascular tumors.¹² A proximal type of ES also has been described. This lesion presents as a deep-seated tumor on the proximal limbs and is associated with more aggressive behavior. It lacks the granulomalike pattern and has more prominent epithelioid and rhabdoid histological presentation.^13-15

Epithelioid sarcoma is a mesenchymal tumor that can display multidirectional differentiation that is primarily epithelial.¹⁶ The precise histogenesis of ES remains unclear, but studies have demonstrated a spectrum of differentiation that ranges from primitive myofibroblast or fibrohistiocytelike cells to those with well-developed epithelial properties.^16,17 Epithelioid sarcoma characteristically coexpresses vimentin and low-molecular-weight CKs such as cell adhesion molecule 5.2. The tumor cells often are immunoreactive for epithelial membrane antigen and more than 50% of cases exhibit remarkable CD34 positivity.¹⁶ More recent studies have further refined the immunophenotype, demonstrating frequent expression of CK8 and CK19 but less commonly CK7, CK20, CK34bE12, and CK5/6.^18-20 Additional studies reported that in 10 of 11 cases, ES was positive for CA 125 on immunohistochemical staining, and 3 of 5 patients also had elevated serum CA 125 levels.^21,22 More recently, Hoshino et al²³ showed elevated serum CA 125 levels in 5 of 7 patients with ES. Cancer antigen 125 is a high-molecular-weight glycoprotein commonly used in the identification of epithelial ovarian carcinomas; however, it also has been described in a number of other neoplasms including carcinomas of the breast, lungs, and colon and lymphoma.^24-27 Although it appears that the addition of CA 125 to a panel of other immunohistochemical stains may be helpful in differentiating ES from other soft tissue sarcomas and serum CA 125 levels may help determine tumor burden, currently the number of cases studied is too small to definitively make that conclusion.^21,23 In our case, the tumor cells were strongly and diffusely positive for CA 125. Serum CA 125 levels were not available.

Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).

Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&E, original magnification ×400).

Cytogenetic studies have failed to identify a consistent chromosomal abnormality in ES.⁵ Some analyses performed by comparative genomic hybridization on isolated cases and small case series indicate that the most frequent alterations involve 8q, 18q11, and 22q11.^13,28,29 The tumor suppressor gene SMARCB1/INI1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1/integrase interactor 1) has been mapped to 22q11, and ES commonly shows absence of nuclear staining for this protein, indicating inactivation.^13-15

Conclusion

Benign fibrohistiocytic proliferations should be included in the differential of histological mimickers of ES. Deep biopsies are essential to differentiate these benign tumors from fibrous histiocytomalike or fibromalike lesions of ES because superficial portions of ES may be well differentiated.

First described by Fetsch et al¹ in 2001, superficial acral fibromyxoma (SAFM) is a rare fibromyxoid mesenchymal tumor that typically affects the fingers and toes with frequent involvement of the nail unit. It is not widely recognized and remains poorly understood. We describe a series of 3 cases of SAFM encountered at our institution and provide a review of the literature on this unique tumor.

Case Reports

Patient 1

A 35-year-old man presented for treatment of a “wart” on the right fifth toe that had increased in size over the last year. He reported that the lesion was mildly painful and occasionally bled or drained clear fluid. He also noted cracking of the nail plate on the same toe. Physical examination revealed a firm, flesh-colored, 3-mm dermal papule on the proximal nail fold of the right fifth toe with subtle flattening of the underlying nail plate (Figure 1). The patient underwent biopsy of the involved proximal nail fold. Histopathology revealed a proliferation of small oval and spindle cells arranged in fascicles and bundles in the dermis (Figure 2). There was extensive mucin deposition associated with the spindle cell proliferation. Additionally, spindle cells and mucin surrounded and entrapped collagen bundles on the periphery of the lesion. Lesional cells were diffusely positive for CD34 and extended to the deep surgical margin (Figure 3). S-100 and factor XIIIa stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Figure 1. Firm dermal papule on the proximal nail fold of the right fifth toe with associated nail plate dystrophy. Figure 2. Small oval and spindle cells arranged in fascicles and bundles in the dermis, with extensive mucin deposition and collagen trapping (H&E, original magnification ×100). Figure 3. Tumor cells were positive on CD34 staining (original magnification ×40). Figure 4. Dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition (H&E, original magnification ×400).

Patient 2

A 47-year-old man presented with an asymptomatic growth on the left fourth toe that had increased in size over the last year. Physical examination revealed an 8-mm, firm, fleshy, flesh-colored, smooth and slightly pedunculated papule on the distal aspect of the left fourth toe. The nail plate and periungual region were not involved. A shave biopsy of the papule was obtained. Histopathology demonstrated dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition throughout the dermis (Figure 4). Lesional cells were positive for CD34. An S-100 stain highlighted dermal dendritic cells, but lesional cells were negative. No further excision was undertaken, and there was no evidence of recurrence at 1-year follow-up. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Patient 3

A 45-year-old woman presented with asymptomatic distal onycholysis of the right thumbnail of 1 year’s duration. She denied any history of trauma, and no bleeding or pigmentary changes were noted. Physical examination revealed a 5-mm flesh-colored papule on the hyponychium of the right thumb with focal onycholysis (Figure 5). A wedge biopsy of the lesion was performed. Histopathology showed an intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (Figure 6). CD34 staining strongly highlighted lesional cells. S-100 and neurofilament stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Comment

Clinically, SAFM typically presents as a slow-growing solitary nodule on the distal fingers or toes. The great toe is the most commonly affected digit, and the tumor may be subungual in up to two-thirds of cases.¹ Unusual locations, such as the heel, also have been reported.² Onset typically occurs in the fifth or sixth decade, and there is an approximately 2-fold higher incidence in men than women.^1-3

Histopathologically, SAFM is a characteristically well-circumscribed but unencapsulated dermal tumor composed of spindle and stellate cells in a loose storiform or fascicular arrangement embedded in a myxoid, myxocollagenous, or collagenous stroma.⁴ The tumor often occupies the entire dermis and may extend into the subcutis or occasionally the underlying fascia and bone.^4,5 Mast cells often are prominent, and microvascular accentuation also may be seen. Inflammatory infiltrates and multinucleated giant cells typically are not seen.⁶ Although 2 cases of atypical SAFM have been described,² cellular atypia is not a characteristic feature of SAFM.

The immunohistochemical profile of SAFM is characterized by diffuse or focal expression of CD34, focal expression of epithelial membrane antigen (EMA), CD99 expression, and varying numbers of factor XIIIa–positive histiocytes.^2,3 Positive staining for vimentin also is common. Staining typically is negative for S-100, human melanoma black 45, keratin, smooth muscle actin, and desmin.

The standard treatment of SAFM is complete local resection of the tumor, though some patients have been treated with partial excision or biopsy and partial or complete digital amputation.¹ Local recurrence may occur in up to 20% of cases; however, approximately two-thirds of the reported recurrences in the literature occurred after incomplete tumor excision.^1,2 It may be more appropriate to consider these cases as persistent rather than recurrent tumors. Superficial acral fibromyxoma is considered a benign tumor, with no known cases of metastases.⁴

Figure 5. A firm flesh-colored papule on the hyponychium of the right thumb prior to biopsy. Figure 6. Intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (H&E, original magnification ×40).

A broad differential diagnosis exists for SAFM and it can be difficult to differentiate it from a wide variety of benign and malignant tumors that may be seen on the nail unit and distal extremities (Table). Myxoid neurofibromas typically present as solitary lesions on the hands and feet. Similar to SAFM, myxoid neurofibromas are unencapsulated dermal tumors composed of spindle-shaped cells in which mast cells often are conspicuous.^2,7 However, tumor cells in myxoid neurofibromas are S-100 positive, and the lesions typically do not show vasculature accentuation.^4,7

Sclerosing perineuriomas are benign fibrous tumors of the fingers and palms. Histopathologically, bland spindle cells arranged in fascicles and whorls are observed in a hyalinized collagen matrix.⁸ Immunohistochemically, sclerosing perineuriomas are positive for EMA and negative for S-100, but unlike SAFM, these tumors usually are CD34 negative.⁸

Superficial angiomyxomas typically are located on the head and neck but also may be found in other locations such as the trunk. They present as cutaneous papules or polypoid lesions. Histopathologically, superficial angiomyxomas are poorly circumscribed with a lobular pattern. Spindle-shaped fibroblasts exist in a myxoid matrix with neutrophils and thin-walled capillaries. The fibroblasts are variably positive for CD34 but also are S-100 positive.^1,9

Myxoid dermatofibrosarcoma protuberans is a rare, locally aggressive, mesenchymal tumor of the skin and subcutis² that typically presents on the trunk, proximal extremities, or head and neck; occurrence on the fingers or toes is exceedingly rare.^2,10 Histopathologically, a myxoid stroma contains sheets of bland spindle-shaped cells with minimal to no atypia, sometimes arranged in a storiform pattern. The tumor characteristically invades deeply into the subcutaneous tissues. CD34 is characteristically positive and S-100 is negative.^2,10

Low-grade myxofibrosarcoma is a soft tissue sarcoma easily confused with other spindle cell tumors. It is one of the most common sarcomas in adults but rarely arises in acral areas.² It is characterized by a nodular growth pattern with marked nuclear atypia and perivascular clustering of tumor cells. CD34 staining may be positive in some cases.¹¹

Similar to SAFM, myxoinflammatory fibroblastic sarcoma has a predilection for the extremities.⁴ However, it typically presents as a subcutaneous mass and has no documented tendency for nail bed involvement. Also unlike SAFM, it has a remarkable inflammatory infiltrate and characteristic virocyte or Reed-Sternberg cells.¹²

Acquired digital fibrokeratomas are benign neoplasms that occur on fingers and toes; the classic clinical presentation is a solitary smooth nodule or dome, often with a characteristic projecting configuration and horn shape.¹ Histopathologically, these tumors are paucicellular with thick, vertically oriented, interwoven collagen bundles; cells may be positive for CD34 but are negative for EMA.^1,13 Related to acquired digital fibrokeratomas are Koenen tumors, which share a similar histology but are distinguished by their clinical characteristics. For example, Koenen tumors tend to be multifocal and are strongly associated with tuberous sclerosis. These tumors also have a tendency to recur.¹

Conclusion

Our report of 3 typical cases of SAFM highlights the need to keep this increasingly recognized and well-defined clinicopathological entity in the differential for slow-growing tumors in acral locations, particularly those in the periungual and subungual regions.

First described by Fetsch et al¹ in 2001, superficial acral fibromyxoma (SAFM) is a rare fibromyxoid mesenchymal tumor that typically affects the fingers and toes with frequent involvement of the nail unit. It is not widely recognized and remains poorly understood. We describe a series of 3 cases of SAFM encountered at our institution and provide a review of the literature on this unique tumor.

Case Reports

Patient 1

A 35-year-old man presented for treatment of a “wart” on the right fifth toe that had increased in size over the last year. He reported that the lesion was mildly painful and occasionally bled or drained clear fluid. He also noted cracking of the nail plate on the same toe. Physical examination revealed a firm, flesh-colored, 3-mm dermal papule on the proximal nail fold of the right fifth toe with subtle flattening of the underlying nail plate (Figure 1). The patient underwent biopsy of the involved proximal nail fold. Histopathology revealed a proliferation of small oval and spindle cells arranged in fascicles and bundles in the dermis (Figure 2). There was extensive mucin deposition associated with the spindle cell proliferation. Additionally, spindle cells and mucin surrounded and entrapped collagen bundles on the periphery of the lesion. Lesional cells were diffusely positive for CD34 and extended to the deep surgical margin (Figure 3). S-100 and factor XIIIa stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Figure 1. Firm dermal papule on the proximal nail fold of the right fifth toe with associated nail plate dystrophy. Figure 2. Small oval and spindle cells arranged in fascicles and bundles in the dermis, with extensive mucin deposition and collagen trapping (H&E, original magnification ×100). Figure 3. Tumor cells were positive on CD34 staining (original magnification ×40). Figure 4. Dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition (H&E, original magnification ×400).

Patient 2

A 47-year-old man presented with an asymptomatic growth on the left fourth toe that had increased in size over the last year. Physical examination revealed an 8-mm, firm, fleshy, flesh-colored, smooth and slightly pedunculated papule on the distal aspect of the left fourth toe. The nail plate and periungual region were not involved. A shave biopsy of the papule was obtained. Histopathology demonstrated dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition throughout the dermis (Figure 4). Lesional cells were positive for CD34. An S-100 stain highlighted dermal dendritic cells, but lesional cells were negative. No further excision was undertaken, and there was no evidence of recurrence at 1-year follow-up. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Patient 3

A 45-year-old woman presented with asymptomatic distal onycholysis of the right thumbnail of 1 year’s duration. She denied any history of trauma, and no bleeding or pigmentary changes were noted. Physical examination revealed a 5-mm flesh-colored papule on the hyponychium of the right thumb with focal onycholysis (Figure 5). A wedge biopsy of the lesion was performed. Histopathology showed an intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (Figure 6). CD34 staining strongly highlighted lesional cells. S-100 and neurofilament stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Comment

Clinically, SAFM typically presents as a slow-growing solitary nodule on the distal fingers or toes. The great toe is the most commonly affected digit, and the tumor may be subungual in up to two-thirds of cases.¹ Unusual locations, such as the heel, also have been reported.² Onset typically occurs in the fifth or sixth decade, and there is an approximately 2-fold higher incidence in men than women.^1-3

Histopathologically, SAFM is a characteristically well-circumscribed but unencapsulated dermal tumor composed of spindle and stellate cells in a loose storiform or fascicular arrangement embedded in a myxoid, myxocollagenous, or collagenous stroma.⁴ The tumor often occupies the entire dermis and may extend into the subcutis or occasionally the underlying fascia and bone.^4,5 Mast cells often are prominent, and microvascular accentuation also may be seen. Inflammatory infiltrates and multinucleated giant cells typically are not seen.⁶ Although 2 cases of atypical SAFM have been described,² cellular atypia is not a characteristic feature of SAFM.

The immunohistochemical profile of SAFM is characterized by diffuse or focal expression of CD34, focal expression of epithelial membrane antigen (EMA), CD99 expression, and varying numbers of factor XIIIa–positive histiocytes.^2,3 Positive staining for vimentin also is common. Staining typically is negative for S-100, human melanoma black 45, keratin, smooth muscle actin, and desmin.

The standard treatment of SAFM is complete local resection of the tumor, though some patients have been treated with partial excision or biopsy and partial or complete digital amputation.¹ Local recurrence may occur in up to 20% of cases; however, approximately two-thirds of the reported recurrences in the literature occurred after incomplete tumor excision.^1,2 It may be more appropriate to consider these cases as persistent rather than recurrent tumors. Superficial acral fibromyxoma is considered a benign tumor, with no known cases of metastases.⁴

Figure 5. A firm flesh-colored papule on the hyponychium of the right thumb prior to biopsy. Figure 6. Intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (H&E, original magnification ×40).

A broad differential diagnosis exists for SAFM and it can be difficult to differentiate it from a wide variety of benign and malignant tumors that may be seen on the nail unit and distal extremities (Table). Myxoid neurofibromas typically present as solitary lesions on the hands and feet. Similar to SAFM, myxoid neurofibromas are unencapsulated dermal tumors composed of spindle-shaped cells in which mast cells often are conspicuous.^2,7 However, tumor cells in myxoid neurofibromas are S-100 positive, and the lesions typically do not show vasculature accentuation.^4,7

Sclerosing perineuriomas are benign fibrous tumors of the fingers and palms. Histopathologically, bland spindle cells arranged in fascicles and whorls are observed in a hyalinized collagen matrix.⁸ Immunohistochemically, sclerosing perineuriomas are positive for EMA and negative for S-100, but unlike SAFM, these tumors usually are CD34 negative.⁸

Superficial angiomyxomas typically are located on the head and neck but also may be found in other locations such as the trunk. They present as cutaneous papules or polypoid lesions. Histopathologically, superficial angiomyxomas are poorly circumscribed with a lobular pattern. Spindle-shaped fibroblasts exist in a myxoid matrix with neutrophils and thin-walled capillaries. The fibroblasts are variably positive for CD34 but also are S-100 positive.^1,9

Myxoid dermatofibrosarcoma protuberans is a rare, locally aggressive, mesenchymal tumor of the skin and subcutis² that typically presents on the trunk, proximal extremities, or head and neck; occurrence on the fingers or toes is exceedingly rare.^2,10 Histopathologically, a myxoid stroma contains sheets of bland spindle-shaped cells with minimal to no atypia, sometimes arranged in a storiform pattern. The tumor characteristically invades deeply into the subcutaneous tissues. CD34 is characteristically positive and S-100 is negative.^2,10

Low-grade myxofibrosarcoma is a soft tissue sarcoma easily confused with other spindle cell tumors. It is one of the most common sarcomas in adults but rarely arises in acral areas.² It is characterized by a nodular growth pattern with marked nuclear atypia and perivascular clustering of tumor cells. CD34 staining may be positive in some cases.¹¹

Similar to SAFM, myxoinflammatory fibroblastic sarcoma has a predilection for the extremities.⁴ However, it typically presents as a subcutaneous mass and has no documented tendency for nail bed involvement. Also unlike SAFM, it has a remarkable inflammatory infiltrate and characteristic virocyte or Reed-Sternberg cells.¹²

Acquired digital fibrokeratomas are benign neoplasms that occur on fingers and toes; the classic clinical presentation is a solitary smooth nodule or dome, often with a characteristic projecting configuration and horn shape.¹ Histopathologically, these tumors are paucicellular with thick, vertically oriented, interwoven collagen bundles; cells may be positive for CD34 but are negative for EMA.^1,13 Related to acquired digital fibrokeratomas are Koenen tumors, which share a similar histology but are distinguished by their clinical characteristics. For example, Koenen tumors tend to be multifocal and are strongly associated with tuberous sclerosis. These tumors also have a tendency to recur.¹

Conclusion

Our report of 3 typical cases of SAFM highlights the need to keep this increasingly recognized and well-defined clinicopathological entity in the differential for slow-growing tumors in acral locations, particularly those in the periungual and subungual regions.

First described by Fetsch et al¹ in 2001, superficial acral fibromyxoma (SAFM) is a rare fibromyxoid mesenchymal tumor that typically affects the fingers and toes with frequent involvement of the nail unit. It is not widely recognized and remains poorly understood. We describe a series of 3 cases of SAFM encountered at our institution and provide a review of the literature on this unique tumor.

Case Reports

Patient 1

A 35-year-old man presented for treatment of a “wart” on the right fifth toe that had increased in size over the last year. He reported that the lesion was mildly painful and occasionally bled or drained clear fluid. He also noted cracking of the nail plate on the same toe. Physical examination revealed a firm, flesh-colored, 3-mm dermal papule on the proximal nail fold of the right fifth toe with subtle flattening of the underlying nail plate (Figure 1). The patient underwent biopsy of the involved proximal nail fold. Histopathology revealed a proliferation of small oval and spindle cells arranged in fascicles and bundles in the dermis (Figure 2). There was extensive mucin deposition associated with the spindle cell proliferation. Additionally, spindle cells and mucin surrounded and entrapped collagen bundles on the periphery of the lesion. Lesional cells were diffusely positive for CD34 and extended to the deep surgical margin (Figure 3). S-100 and factor XIIIa stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Figure 1. Firm dermal papule on the proximal nail fold of the right fifth toe with associated nail plate dystrophy. Figure 2. Small oval and spindle cells arranged in fascicles and bundles in the dermis, with extensive mucin deposition and collagen trapping (H&E, original magnification ×100). Figure 3. Tumor cells were positive on CD34 staining (original magnification ×40). Figure 4. Dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition (H&E, original magnification ×400).

Patient 2

A 47-year-old man presented with an asymptomatic growth on the left fourth toe that had increased in size over the last year. Physical examination revealed an 8-mm, firm, fleshy, flesh-colored, smooth and slightly pedunculated papule on the distal aspect of the left fourth toe. The nail plate and periungual region were not involved. A shave biopsy of the papule was obtained. Histopathology demonstrated dermal stellate spindle cells arranged in a loose fascicular pattern with marked mucin deposition throughout the dermis (Figure 4). Lesional cells were positive for CD34. An S-100 stain highlighted dermal dendritic cells, but lesional cells were negative. No further excision was undertaken, and there was no evidence of recurrence at 1-year follow-up. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Patient 3

A 45-year-old woman presented with asymptomatic distal onycholysis of the right thumbnail of 1 year’s duration. She denied any history of trauma, and no bleeding or pigmentary changes were noted. Physical examination revealed a 5-mm flesh-colored papule on the hyponychium of the right thumb with focal onycholysis (Figure 5). A wedge biopsy of the lesion was performed. Histopathology showed an intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (Figure 6). CD34 staining strongly highlighted lesional cells. S-100 and neurofilament stains were negative. The diagnosis of SAFM was made based on the acral location, histopathologic appearance, and immunohistochemical profile of the tumor.

Comment

Clinically, SAFM typically presents as a slow-growing solitary nodule on the distal fingers or toes. The great toe is the most commonly affected digit, and the tumor may be subungual in up to two-thirds of cases.¹ Unusual locations, such as the heel, also have been reported.² Onset typically occurs in the fifth or sixth decade, and there is an approximately 2-fold higher incidence in men than women.^1-3

Histopathologically, SAFM is a characteristically well-circumscribed but unencapsulated dermal tumor composed of spindle and stellate cells in a loose storiform or fascicular arrangement embedded in a myxoid, myxocollagenous, or collagenous stroma.⁴ The tumor often occupies the entire dermis and may extend into the subcutis or occasionally the underlying fascia and bone.^4,5 Mast cells often are prominent, and microvascular accentuation also may be seen. Inflammatory infiltrates and multinucleated giant cells typically are not seen.⁶ Although 2 cases of atypical SAFM have been described,² cellular atypia is not a characteristic feature of SAFM.

The immunohistochemical profile of SAFM is characterized by diffuse or focal expression of CD34, focal expression of epithelial membrane antigen (EMA), CD99 expression, and varying numbers of factor XIIIa–positive histiocytes.^2,3 Positive staining for vimentin also is common. Staining typically is negative for S-100, human melanoma black 45, keratin, smooth muscle actin, and desmin.

The standard treatment of SAFM is complete local resection of the tumor, though some patients have been treated with partial excision or biopsy and partial or complete digital amputation.¹ Local recurrence may occur in up to 20% of cases; however, approximately two-thirds of the reported recurrences in the literature occurred after incomplete tumor excision.^1,2 It may be more appropriate to consider these cases as persistent rather than recurrent tumors. Superficial acral fibromyxoma is considered a benign tumor, with no known cases of metastases.⁴

Figure 5. A firm flesh-colored papule on the hyponychium of the right thumb prior to biopsy. Figure 6. Intradermal nodular proliferation of bland spindle cells arranged in loose fascicles and bundles and embedded in a myxoid stroma (H&E, original magnification ×40).

A broad differential diagnosis exists for SAFM and it can be difficult to differentiate it from a wide variety of benign and malignant tumors that may be seen on the nail unit and distal extremities (Table). Myxoid neurofibromas typically present as solitary lesions on the hands and feet. Similar to SAFM, myxoid neurofibromas are unencapsulated dermal tumors composed of spindle-shaped cells in which mast cells often are conspicuous.^2,7 However, tumor cells in myxoid neurofibromas are S-100 positive, and the lesions typically do not show vasculature accentuation.^4,7

Sclerosing perineuriomas are benign fibrous tumors of the fingers and palms. Histopathologically, bland spindle cells arranged in fascicles and whorls are observed in a hyalinized collagen matrix.⁸ Immunohistochemically, sclerosing perineuriomas are positive for EMA and negative for S-100, but unlike SAFM, these tumors usually are CD34 negative.⁸

Superficial angiomyxomas typically are located on the head and neck but also may be found in other locations such as the trunk. They present as cutaneous papules or polypoid lesions. Histopathologically, superficial angiomyxomas are poorly circumscribed with a lobular pattern. Spindle-shaped fibroblasts exist in a myxoid matrix with neutrophils and thin-walled capillaries. The fibroblasts are variably positive for CD34 but also are S-100 positive.^1,9

Myxoid dermatofibrosarcoma protuberans is a rare, locally aggressive, mesenchymal tumor of the skin and subcutis² that typically presents on the trunk, proximal extremities, or head and neck; occurrence on the fingers or toes is exceedingly rare.^2,10 Histopathologically, a myxoid stroma contains sheets of bland spindle-shaped cells with minimal to no atypia, sometimes arranged in a storiform pattern. The tumor characteristically invades deeply into the subcutaneous tissues. CD34 is characteristically positive and S-100 is negative.^2,10

Low-grade myxofibrosarcoma is a soft tissue sarcoma easily confused with other spindle cell tumors. It is one of the most common sarcomas in adults but rarely arises in acral areas.² It is characterized by a nodular growth pattern with marked nuclear atypia and perivascular clustering of tumor cells. CD34 staining may be positive in some cases.¹¹

Similar to SAFM, myxoinflammatory fibroblastic sarcoma has a predilection for the extremities.⁴ However, it typically presents as a subcutaneous mass and has no documented tendency for nail bed involvement. Also unlike SAFM, it has a remarkable inflammatory infiltrate and characteristic virocyte or Reed-Sternberg cells.¹²

Acquired digital fibrokeratomas are benign neoplasms that occur on fingers and toes; the classic clinical presentation is a solitary smooth nodule or dome, often with a characteristic projecting configuration and horn shape.¹ Histopathologically, these tumors are paucicellular with thick, vertically oriented, interwoven collagen bundles; cells may be positive for CD34 but are negative for EMA.^1,13 Related to acquired digital fibrokeratomas are Koenen tumors, which share a similar histology but are distinguished by their clinical characteristics. For example, Koenen tumors tend to be multifocal and are strongly associated with tuberous sclerosis. These tumors also have a tendency to recur.¹

Conclusion

Our report of 3 typical cases of SAFM highlights the need to keep this increasingly recognized and well-defined clinicopathological entity in the differential for slow-growing tumors in acral locations, particularly those in the periungual and subungual regions.