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The Diagnosis: Nodular Basal Cell Carcinoma

Histopathology of the lesion showed a large basaloid lobule with focal epidermal attachment, peripheral nuclear palisading with cleft formation between the tumor and surrounding stroma, fibromyxoid stroma and mild pleomorphism, and variable mitotic activity and apoptosis (Figure). Based on the clinical presentation and histopathology, the patient was diagnosed with nodular basal cell carcinoma (BCC). He underwent a wide local excision of the affected area that was repaired with a splitthickness skin graft.

CT113005199_Fig_ABCD.jpg

Basal cell carcinoma is the most common skin cancer worldwide and typically occurs due to years of UV radiation damage on sun-exposed skin, which accounts for a higher frequency of BCC occurring in patients residing in geographic locations with greater UV exposure (eg, higher and lower latitudes). In addition to cumulative UV dose, the duration of the exposure as well as its intensity also play a role in the development of BCC, particularly in early childhood and adolescence. Nevertheless, UV exposure is not the only risk factor, as 20% of BCCs arise in skin that is not exposed to the sun. Other risk factors include exposure to ionizing radiation and arsenic, immunosuppression, and genetic predisposition.¹ Although these malignancies typically do not metastasize, growth can lead to local tissue destruction and major disfigurement if not treated in a timely fashion.²

In our patient, the differential diagnosis included pyoderma gangrenosum (PG) given the clinical appearance of the cribriform base and violaceous undermined rim of the ulcer. Pyoderma gangrenosum is a rare neutrophilic disorder that often results in ulcers that have been associated with various systemic autoimmune and inflammatory conditions, such as inflammatory bowel disease. There are 4 main subtypes of PG: the classic ulcerative type (our patient); the pustular type, which most often is seen in patients with inflammatory bowel disease; the bullous type, which can be seen in patients with an associated lymphoproliferative disorder; and the vegetative type. It frequently is thought of as both a clinical and histologic diagnosis of exclusion due to the nonspecific histopathologic features; most lesions demonstrate an infiltrate of neutrophils in the dermis. A biopsy was crucial in our patient, considering that diagnosis and treatment would have been further delayed had the patient been empirically treated with oral and topical steroids for presumed PG, which is precisely why PG is a diagnosis of exclusion. It is imperative for clinicians to rule out other pathologies, such as infection or malignancy, as demonstrated in our patient. The progressive onset and slow evolution of the lesion over years along with a lack of pain were more suggestive of BCC rather than PG. However, there is a report in the literature of PG mimicking BCC with both clinical and dermoscopic findings.³

Venous or stasis ulcers are painless, and although they rarely occur on the calf, they typically are seen lower on the leg such as on the medial ankles. Our patient endorsed occasional swelling of the affected leg and presented with edema, but overlying stasis change and other signs of venous insufficiency were absent.

Buruli ulcer is a painless chronic debilitating cutaneous disease resulting in indolent necrotizing skin as well as subcutaneous and bone lesions. It is caused by the environmental organism Mycobacterium ulcerans and typically is reported in Africa, Central/South America, the Western Pacific Region, and Australia.⁴ Histopathology usually demonstrates necrosis of subcutaneous tissue and dermal collagen accompanied by inflammation and acidfast bacilli highlighted by Ziehl-Neelsen stain.⁵ Smears of the lesions as well as culture and polymerase chain reaction for acid-fast bacilli also can be performed. Our patient reported no recent travel to any endemic areas and had no other risk factors or exposures to the pathogen responsible for this condition.

Traumatic ulcer also was included in the differential diagnosis, but the patient denied preceding trauma to the area, and the contralateral foot prosthesis did not rub on or impact the affected leg.

Basal cell carcinoma typically is treated surgically, but choice of treatment can depend on the subtype, size, tumor site, and/or patient preference.¹ Other treatment modalities include electrodesiccation and curettage, cryosurgical destruction, photodynamic therapy, radiation, topical therapies, and systemic medications. Radiotherapy can be considered as a primary treatment option for BCC if surgery is contraindicated or declined by the patient, but it also is useful as an adjuvant therapy when there is perineural invasion of the tumor or positive margins. Hedgehog pathway inhibitors such as vismodegib currently are indicated for patients who are not candidates for surgery or radiation as well as for those with metastatic or locally advanced, recurrent BCC. There is no single treatment method ideal for every lesion or patient. Specific populations such as the elderly, the immunosuppressed, or those with poor baseline functional status may warrant a nonsurgical approach. The clinician must take into consideration all factors while at the same time thinking about how to best accomplish the goals of recurrencefree tumor removal, correction of any underlying functional impairment from the tumor, and maintenance of cosmesis.¹

The Diagnosis: Nodular Basal Cell Carcinoma

Histopathology of the lesion showed a large basaloid lobule with focal epidermal attachment, peripheral nuclear palisading with cleft formation between the tumor and surrounding stroma, fibromyxoid stroma and mild pleomorphism, and variable mitotic activity and apoptosis (Figure). Based on the clinical presentation and histopathology, the patient was diagnosed with nodular basal cell carcinoma (BCC). He underwent a wide local excision of the affected area that was repaired with a splitthickness skin graft.

CT113005199_Fig_ABCD.jpg

Basal cell carcinoma is the most common skin cancer worldwide and typically occurs due to years of UV radiation damage on sun-exposed skin, which accounts for a higher frequency of BCC occurring in patients residing in geographic locations with greater UV exposure (eg, higher and lower latitudes). In addition to cumulative UV dose, the duration of the exposure as well as its intensity also play a role in the development of BCC, particularly in early childhood and adolescence. Nevertheless, UV exposure is not the only risk factor, as 20% of BCCs arise in skin that is not exposed to the sun. Other risk factors include exposure to ionizing radiation and arsenic, immunosuppression, and genetic predisposition.¹ Although these malignancies typically do not metastasize, growth can lead to local tissue destruction and major disfigurement if not treated in a timely fashion.²

In our patient, the differential diagnosis included pyoderma gangrenosum (PG) given the clinical appearance of the cribriform base and violaceous undermined rim of the ulcer. Pyoderma gangrenosum is a rare neutrophilic disorder that often results in ulcers that have been associated with various systemic autoimmune and inflammatory conditions, such as inflammatory bowel disease. There are 4 main subtypes of PG: the classic ulcerative type (our patient); the pustular type, which most often is seen in patients with inflammatory bowel disease; the bullous type, which can be seen in patients with an associated lymphoproliferative disorder; and the vegetative type. It frequently is thought of as both a clinical and histologic diagnosis of exclusion due to the nonspecific histopathologic features; most lesions demonstrate an infiltrate of neutrophils in the dermis. A biopsy was crucial in our patient, considering that diagnosis and treatment would have been further delayed had the patient been empirically treated with oral and topical steroids for presumed PG, which is precisely why PG is a diagnosis of exclusion. It is imperative for clinicians to rule out other pathologies, such as infection or malignancy, as demonstrated in our patient. The progressive onset and slow evolution of the lesion over years along with a lack of pain were more suggestive of BCC rather than PG. However, there is a report in the literature of PG mimicking BCC with both clinical and dermoscopic findings.³

Venous or stasis ulcers are painless, and although they rarely occur on the calf, they typically are seen lower on the leg such as on the medial ankles. Our patient endorsed occasional swelling of the affected leg and presented with edema, but overlying stasis change and other signs of venous insufficiency were absent.

Buruli ulcer is a painless chronic debilitating cutaneous disease resulting in indolent necrotizing skin as well as subcutaneous and bone lesions. It is caused by the environmental organism Mycobacterium ulcerans and typically is reported in Africa, Central/South America, the Western Pacific Region, and Australia.⁴ Histopathology usually demonstrates necrosis of subcutaneous tissue and dermal collagen accompanied by inflammation and acidfast bacilli highlighted by Ziehl-Neelsen stain.⁵ Smears of the lesions as well as culture and polymerase chain reaction for acid-fast bacilli also can be performed. Our patient reported no recent travel to any endemic areas and had no other risk factors or exposures to the pathogen responsible for this condition.

Traumatic ulcer also was included in the differential diagnosis, but the patient denied preceding trauma to the area, and the contralateral foot prosthesis did not rub on or impact the affected leg.

Basal cell carcinoma typically is treated surgically, but choice of treatment can depend on the subtype, size, tumor site, and/or patient preference.¹ Other treatment modalities include electrodesiccation and curettage, cryosurgical destruction, photodynamic therapy, radiation, topical therapies, and systemic medications. Radiotherapy can be considered as a primary treatment option for BCC if surgery is contraindicated or declined by the patient, but it also is useful as an adjuvant therapy when there is perineural invasion of the tumor or positive margins. Hedgehog pathway inhibitors such as vismodegib currently are indicated for patients who are not candidates for surgery or radiation as well as for those with metastatic or locally advanced, recurrent BCC. There is no single treatment method ideal for every lesion or patient. Specific populations such as the elderly, the immunosuppressed, or those with poor baseline functional status may warrant a nonsurgical approach. The clinician must take into consideration all factors while at the same time thinking about how to best accomplish the goals of recurrencefree tumor removal, correction of any underlying functional impairment from the tumor, and maintenance of cosmesis.¹

The Diagnosis: Nodular Basal Cell Carcinoma

Histopathology of the lesion showed a large basaloid lobule with focal epidermal attachment, peripheral nuclear palisading with cleft formation between the tumor and surrounding stroma, fibromyxoid stroma and mild pleomorphism, and variable mitotic activity and apoptosis (Figure). Based on the clinical presentation and histopathology, the patient was diagnosed with nodular basal cell carcinoma (BCC). He underwent a wide local excision of the affected area that was repaired with a splitthickness skin graft.

CT113005199_Fig_ABCD.jpg

Basal cell carcinoma is the most common skin cancer worldwide and typically occurs due to years of UV radiation damage on sun-exposed skin, which accounts for a higher frequency of BCC occurring in patients residing in geographic locations with greater UV exposure (eg, higher and lower latitudes). In addition to cumulative UV dose, the duration of the exposure as well as its intensity also play a role in the development of BCC, particularly in early childhood and adolescence. Nevertheless, UV exposure is not the only risk factor, as 20% of BCCs arise in skin that is not exposed to the sun. Other risk factors include exposure to ionizing radiation and arsenic, immunosuppression, and genetic predisposition.¹ Although these malignancies typically do not metastasize, growth can lead to local tissue destruction and major disfigurement if not treated in a timely fashion.²

In our patient, the differential diagnosis included pyoderma gangrenosum (PG) given the clinical appearance of the cribriform base and violaceous undermined rim of the ulcer. Pyoderma gangrenosum is a rare neutrophilic disorder that often results in ulcers that have been associated with various systemic autoimmune and inflammatory conditions, such as inflammatory bowel disease. There are 4 main subtypes of PG: the classic ulcerative type (our patient); the pustular type, which most often is seen in patients with inflammatory bowel disease; the bullous type, which can be seen in patients with an associated lymphoproliferative disorder; and the vegetative type. It frequently is thought of as both a clinical and histologic diagnosis of exclusion due to the nonspecific histopathologic features; most lesions demonstrate an infiltrate of neutrophils in the dermis. A biopsy was crucial in our patient, considering that diagnosis and treatment would have been further delayed had the patient been empirically treated with oral and topical steroids for presumed PG, which is precisely why PG is a diagnosis of exclusion. It is imperative for clinicians to rule out other pathologies, such as infection or malignancy, as demonstrated in our patient. The progressive onset and slow evolution of the lesion over years along with a lack of pain were more suggestive of BCC rather than PG. However, there is a report in the literature of PG mimicking BCC with both clinical and dermoscopic findings.³

Venous or stasis ulcers are painless, and although they rarely occur on the calf, they typically are seen lower on the leg such as on the medial ankles. Our patient endorsed occasional swelling of the affected leg and presented with edema, but overlying stasis change and other signs of venous insufficiency were absent.

Buruli ulcer is a painless chronic debilitating cutaneous disease resulting in indolent necrotizing skin as well as subcutaneous and bone lesions. It is caused by the environmental organism Mycobacterium ulcerans and typically is reported in Africa, Central/South America, the Western Pacific Region, and Australia.⁴ Histopathology usually demonstrates necrosis of subcutaneous tissue and dermal collagen accompanied by inflammation and acidfast bacilli highlighted by Ziehl-Neelsen stain.⁵ Smears of the lesions as well as culture and polymerase chain reaction for acid-fast bacilli also can be performed. Our patient reported no recent travel to any endemic areas and had no other risk factors or exposures to the pathogen responsible for this condition.

Traumatic ulcer also was included in the differential diagnosis, but the patient denied preceding trauma to the area, and the contralateral foot prosthesis did not rub on or impact the affected leg.

Basal cell carcinoma typically is treated surgically, but choice of treatment can depend on the subtype, size, tumor site, and/or patient preference.¹ Other treatment modalities include electrodesiccation and curettage, cryosurgical destruction, photodynamic therapy, radiation, topical therapies, and systemic medications. Radiotherapy can be considered as a primary treatment option for BCC if surgery is contraindicated or declined by the patient, but it also is useful as an adjuvant therapy when there is perineural invasion of the tumor or positive margins. Hedgehog pathway inhibitors such as vismodegib currently are indicated for patients who are not candidates for surgery or radiation as well as for those with metastatic or locally advanced, recurrent BCC. There is no single treatment method ideal for every lesion or patient. Specific populations such as the elderly, the immunosuppressed, or those with poor baseline functional status may warrant a nonsurgical approach. The clinician must take into consideration all factors while at the same time thinking about how to best accomplish the goals of recurrencefree tumor removal, correction of any underlying functional impairment from the tumor, and maintenance of cosmesis.¹

The Diagnosis: Subcutaneous Fat Necrosis

Histopathology revealed lobular panniculitis with lymphohistiocytic inflammation, lipid crystals, and calcifications in our patient (Figure). Subcutaneous fat necrosis (SCFN) was diagnosed based on these characteristic histopathologic findings. No further treatment was pursued.

CT113004027_figAB.jpg

Subcutaneous fat necrosis is a rare, self-limiting panniculitis that typically resolves within several weeks to months without scarring. It manifests as red or violaceous subcutaneous nodules or plaques most commonly on the buttocks, trunk, proximal arms and legs, and cheeks.¹ Histopathology reveals lobular panniculitis with dense granulomatous infiltrates of histiocytes, eosinophils, and multinucleated giant cells with needle-shaped crystals. Focal areas of fat necrosis with calcification also can be seen.²

The epidemiology of SCFN is unknown. Most cases occur in healthy full-term to postterm neonates who experience hypoxia, other prenatal stressors, or therapeutic hypothermia for the treatment of hypoxic-ischemic encephalopathy.³ Although the etiology is unclear, certain inciting factors such as local tissue hypoxia, cold exposure, meconium aspiration, maternal diabetes, preeclampsia, and mechanical pressure have been proposed. Our patient underwent hypothermic cooling protocol, and it has been suggested that the increased saturated to unsaturated fat concentration in the skin of newborns increases the melting point, thus predisposing them to fat crystalization.⁴ Cases of SCFN involving the scalp are rare; therefore, any newborns receiving hypothermic therapy for hypoxic-ischemic encephalopathy should have a thorough skin examination with possible biopsy of lesions that are characteristic of SCFN, such as red or violaceous subcutaneous nodules or plaques, for specific disease identification.

The main complication of SCFN is hypercalcemia, which occurs in approximately 50% of cases. Other serum abnormalities include hyperglycemia, hypertriglyceridemia, and thrombocytopenia, though these findings are not as well associated.⁴ Patients with associated hypercalcemia may be asymptomatic, as in our patient, but other presentations include irritability, weakness, anorexia, vomiting, renal failure, failure to thrive, and encephalopathy. Nephrocalcinosis is a common complication of severe hypercalcemia; however, there is little evidence of associated major renal dysfunction.⁵ The exact mechanism of hypercalcemia is poorly understood. A widely accepted theory postulates that a granulomatous inflammatory infiltrate upregulates 1-α-hydroxylase activity, which enzymatically converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxycholecalciferol, which increases bone resorption and calcium absorption through the gastrointestinal tract and renal systems. Treatments for hypercalcemia include hyperhydration, calcium-wasting diuretics, and low calcium intake.⁶ Furthermore, calcium levels should be obtained at the time of diagnosis and 30, 45, and 60 days after the lesions resolve.⁴

Subcutaneous fat necrosis needs to be differentiated from the more severe panniculitis, sclerema neonatorum (SN), which typically affects critically ill, preterm, and small-for-gestational-age newborns. It is associated with a high mortality rate and is characterized by skin and subadjacent tissue structures. The process typically begins in the thighs, buttocks, or trunk and spreads diffusely, sparing the fat-free palms, soles, and genitalia.⁷ Although our patient was born preterm, the physical characteristics of the nodule and the lack of severe illness placed SN lower on our differential. Histopathologic differences between SCFN and SN involve the extent of tissue fibrosis and presence of inflammatory cells. Sclerema neonatorum typically manifests with thickened connective tissue with a sparse inflammatory infiltrate, including lymphocytes, histiocytes, and multinucleated giant cells.⁷ Conversely, SCFN manifests with fat necrosis with an extensive inflammatory infiltrate. It is important to be able to distinguish between these 2 conditions, as both have vastly different prognoses.

Cold panniculitis, sometimes called “popsicle panniculitis,” is a phenomenon in which cold contact with the skin causes eruption of firm, erythematous, indurated plaques at the site of exposure. This self-limiting condition typically appears hours to days after cold exposure and spontaneously resolves in a few weeks.⁸ Therapeutic hypothermic protocol treatment involves using cooling devices to lower the body temperature for a short duration. The temperature typically is lowered to approximately 32 °C to 36 °C. These temperatures are not low enough to induce cold panniculitis, which is more commonly seen in facial ice applications when managing supraventricular tachycardia in neonates.

Cephalohematoma is a birthing injury that causes blood accumulation within the subperiosteal space. During parturition, the compressive and sheering forces on the calvarium rupture the vessels passing through the periosteum, causing blood to pool slowly into the subperiostium; thus, a cephalohematoma usually manifests later at 1 to 3 days of life as localized head swelling.⁹ The bleeding typically does not cross suture lines and is primarily found in the occipital or parietal regions. The incidence has been reported to be 0.4% to 2.5% of all live births.¹⁰ Although the location of the nodule in our patient was in the occipital region, imaging and biopsy results did not show hemorrhagic findings consistent with cephalohematoma. Management of cephalohematoma mainly is observational, as the mass slowly regresses and the accumulated blood gradually is reabsorbed.

Fungal scalp infections (tinea capitis) are common in the pediatric population. The peak incidence of this infection has been reported in children aged 3 to 7 years, with Trichophyton tonsurans and Microsporum canis as the usual causative organisms.¹¹ Clinical features of tinea capitis include scaly patches with hair loss, hair loss with black pigmented dots at the follicular openings, diffuse scalp scaling with subtle hair loss, and cervical lymphadenopathy.¹² Although less common, tinea capitis can progress to a more severe form known as a kerion, which is characterized by a tender plaque with pustules and crusting. A kerion can result in permanent scarring and alopecia if left untreated.¹² In our patient, a nodule with scaling and faint erythema was observed, but no black pigmented dots at the follicular orifices were present. Therefore, a potassium hydroxide wet mount preparation used to diagnose tinea capitis was unnecessary. Systemic oral antifungal therapy such as fluconazole or terbinafine is the standard treatment for tinea capitis.

The Diagnosis: Subcutaneous Fat Necrosis

Histopathology revealed lobular panniculitis with lymphohistiocytic inflammation, lipid crystals, and calcifications in our patient (Figure). Subcutaneous fat necrosis (SCFN) was diagnosed based on these characteristic histopathologic findings. No further treatment was pursued.

CT113004027_figAB.jpg

Subcutaneous fat necrosis is a rare, self-limiting panniculitis that typically resolves within several weeks to months without scarring. It manifests as red or violaceous subcutaneous nodules or plaques most commonly on the buttocks, trunk, proximal arms and legs, and cheeks.¹ Histopathology reveals lobular panniculitis with dense granulomatous infiltrates of histiocytes, eosinophils, and multinucleated giant cells with needle-shaped crystals. Focal areas of fat necrosis with calcification also can be seen.²

The epidemiology of SCFN is unknown. Most cases occur in healthy full-term to postterm neonates who experience hypoxia, other prenatal stressors, or therapeutic hypothermia for the treatment of hypoxic-ischemic encephalopathy.³ Although the etiology is unclear, certain inciting factors such as local tissue hypoxia, cold exposure, meconium aspiration, maternal diabetes, preeclampsia, and mechanical pressure have been proposed. Our patient underwent hypothermic cooling protocol, and it has been suggested that the increased saturated to unsaturated fat concentration in the skin of newborns increases the melting point, thus predisposing them to fat crystalization.⁴ Cases of SCFN involving the scalp are rare; therefore, any newborns receiving hypothermic therapy for hypoxic-ischemic encephalopathy should have a thorough skin examination with possible biopsy of lesions that are characteristic of SCFN, such as red or violaceous subcutaneous nodules or plaques, for specific disease identification.

The main complication of SCFN is hypercalcemia, which occurs in approximately 50% of cases. Other serum abnormalities include hyperglycemia, hypertriglyceridemia, and thrombocytopenia, though these findings are not as well associated.⁴ Patients with associated hypercalcemia may be asymptomatic, as in our patient, but other presentations include irritability, weakness, anorexia, vomiting, renal failure, failure to thrive, and encephalopathy. Nephrocalcinosis is a common complication of severe hypercalcemia; however, there is little evidence of associated major renal dysfunction.⁵ The exact mechanism of hypercalcemia is poorly understood. A widely accepted theory postulates that a granulomatous inflammatory infiltrate upregulates 1-α-hydroxylase activity, which enzymatically converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxycholecalciferol, which increases bone resorption and calcium absorption through the gastrointestinal tract and renal systems. Treatments for hypercalcemia include hyperhydration, calcium-wasting diuretics, and low calcium intake.⁶ Furthermore, calcium levels should be obtained at the time of diagnosis and 30, 45, and 60 days after the lesions resolve.⁴

Subcutaneous fat necrosis needs to be differentiated from the more severe panniculitis, sclerema neonatorum (SN), which typically affects critically ill, preterm, and small-for-gestational-age newborns. It is associated with a high mortality rate and is characterized by skin and subadjacent tissue structures. The process typically begins in the thighs, buttocks, or trunk and spreads diffusely, sparing the fat-free palms, soles, and genitalia.⁷ Although our patient was born preterm, the physical characteristics of the nodule and the lack of severe illness placed SN lower on our differential. Histopathologic differences between SCFN and SN involve the extent of tissue fibrosis and presence of inflammatory cells. Sclerema neonatorum typically manifests with thickened connective tissue with a sparse inflammatory infiltrate, including lymphocytes, histiocytes, and multinucleated giant cells.⁷ Conversely, SCFN manifests with fat necrosis with an extensive inflammatory infiltrate. It is important to be able to distinguish between these 2 conditions, as both have vastly different prognoses.

Cold panniculitis, sometimes called “popsicle panniculitis,” is a phenomenon in which cold contact with the skin causes eruption of firm, erythematous, indurated plaques at the site of exposure. This self-limiting condition typically appears hours to days after cold exposure and spontaneously resolves in a few weeks.⁸ Therapeutic hypothermic protocol treatment involves using cooling devices to lower the body temperature for a short duration. The temperature typically is lowered to approximately 32 °C to 36 °C. These temperatures are not low enough to induce cold panniculitis, which is more commonly seen in facial ice applications when managing supraventricular tachycardia in neonates.

Cephalohematoma is a birthing injury that causes blood accumulation within the subperiosteal space. During parturition, the compressive and sheering forces on the calvarium rupture the vessels passing through the periosteum, causing blood to pool slowly into the subperiostium; thus, a cephalohematoma usually manifests later at 1 to 3 days of life as localized head swelling.⁹ The bleeding typically does not cross suture lines and is primarily found in the occipital or parietal regions. The incidence has been reported to be 0.4% to 2.5% of all live births.¹⁰ Although the location of the nodule in our patient was in the occipital region, imaging and biopsy results did not show hemorrhagic findings consistent with cephalohematoma. Management of cephalohematoma mainly is observational, as the mass slowly regresses and the accumulated blood gradually is reabsorbed.

Fungal scalp infections (tinea capitis) are common in the pediatric population. The peak incidence of this infection has been reported in children aged 3 to 7 years, with Trichophyton tonsurans and Microsporum canis as the usual causative organisms.¹¹ Clinical features of tinea capitis include scaly patches with hair loss, hair loss with black pigmented dots at the follicular openings, diffuse scalp scaling with subtle hair loss, and cervical lymphadenopathy.¹² Although less common, tinea capitis can progress to a more severe form known as a kerion, which is characterized by a tender plaque with pustules and crusting. A kerion can result in permanent scarring and alopecia if left untreated.¹² In our patient, a nodule with scaling and faint erythema was observed, but no black pigmented dots at the follicular orifices were present. Therefore, a potassium hydroxide wet mount preparation used to diagnose tinea capitis was unnecessary. Systemic oral antifungal therapy such as fluconazole or terbinafine is the standard treatment for tinea capitis.

The Diagnosis: Subcutaneous Fat Necrosis

Histopathology revealed lobular panniculitis with lymphohistiocytic inflammation, lipid crystals, and calcifications in our patient (Figure). Subcutaneous fat necrosis (SCFN) was diagnosed based on these characteristic histopathologic findings. No further treatment was pursued.

CT113004027_figAB.jpg

Subcutaneous fat necrosis is a rare, self-limiting panniculitis that typically resolves within several weeks to months without scarring. It manifests as red or violaceous subcutaneous nodules or plaques most commonly on the buttocks, trunk, proximal arms and legs, and cheeks.¹ Histopathology reveals lobular panniculitis with dense granulomatous infiltrates of histiocytes, eosinophils, and multinucleated giant cells with needle-shaped crystals. Focal areas of fat necrosis with calcification also can be seen.²

The epidemiology of SCFN is unknown. Most cases occur in healthy full-term to postterm neonates who experience hypoxia, other prenatal stressors, or therapeutic hypothermia for the treatment of hypoxic-ischemic encephalopathy.³ Although the etiology is unclear, certain inciting factors such as local tissue hypoxia, cold exposure, meconium aspiration, maternal diabetes, preeclampsia, and mechanical pressure have been proposed. Our patient underwent hypothermic cooling protocol, and it has been suggested that the increased saturated to unsaturated fat concentration in the skin of newborns increases the melting point, thus predisposing them to fat crystalization.⁴ Cases of SCFN involving the scalp are rare; therefore, any newborns receiving hypothermic therapy for hypoxic-ischemic encephalopathy should have a thorough skin examination with possible biopsy of lesions that are characteristic of SCFN, such as red or violaceous subcutaneous nodules or plaques, for specific disease identification.

The main complication of SCFN is hypercalcemia, which occurs in approximately 50% of cases. Other serum abnormalities include hyperglycemia, hypertriglyceridemia, and thrombocytopenia, though these findings are not as well associated.⁴ Patients with associated hypercalcemia may be asymptomatic, as in our patient, but other presentations include irritability, weakness, anorexia, vomiting, renal failure, failure to thrive, and encephalopathy. Nephrocalcinosis is a common complication of severe hypercalcemia; however, there is little evidence of associated major renal dysfunction.⁵ The exact mechanism of hypercalcemia is poorly understood. A widely accepted theory postulates that a granulomatous inflammatory infiltrate upregulates 1-α-hydroxylase activity, which enzymatically converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxycholecalciferol, which increases bone resorption and calcium absorption through the gastrointestinal tract and renal systems. Treatments for hypercalcemia include hyperhydration, calcium-wasting diuretics, and low calcium intake.⁶ Furthermore, calcium levels should be obtained at the time of diagnosis and 30, 45, and 60 days after the lesions resolve.⁴

Subcutaneous fat necrosis needs to be differentiated from the more severe panniculitis, sclerema neonatorum (SN), which typically affects critically ill, preterm, and small-for-gestational-age newborns. It is associated with a high mortality rate and is characterized by skin and subadjacent tissue structures. The process typically begins in the thighs, buttocks, or trunk and spreads diffusely, sparing the fat-free palms, soles, and genitalia.⁷ Although our patient was born preterm, the physical characteristics of the nodule and the lack of severe illness placed SN lower on our differential. Histopathologic differences between SCFN and SN involve the extent of tissue fibrosis and presence of inflammatory cells. Sclerema neonatorum typically manifests with thickened connective tissue with a sparse inflammatory infiltrate, including lymphocytes, histiocytes, and multinucleated giant cells.⁷ Conversely, SCFN manifests with fat necrosis with an extensive inflammatory infiltrate. It is important to be able to distinguish between these 2 conditions, as both have vastly different prognoses.

Cold panniculitis, sometimes called “popsicle panniculitis,” is a phenomenon in which cold contact with the skin causes eruption of firm, erythematous, indurated plaques at the site of exposure. This self-limiting condition typically appears hours to days after cold exposure and spontaneously resolves in a few weeks.⁸ Therapeutic hypothermic protocol treatment involves using cooling devices to lower the body temperature for a short duration. The temperature typically is lowered to approximately 32 °C to 36 °C. These temperatures are not low enough to induce cold panniculitis, which is more commonly seen in facial ice applications when managing supraventricular tachycardia in neonates.

Cephalohematoma is a birthing injury that causes blood accumulation within the subperiosteal space. During parturition, the compressive and sheering forces on the calvarium rupture the vessels passing through the periosteum, causing blood to pool slowly into the subperiostium; thus, a cephalohematoma usually manifests later at 1 to 3 days of life as localized head swelling.⁹ The bleeding typically does not cross suture lines and is primarily found in the occipital or parietal regions. The incidence has been reported to be 0.4% to 2.5% of all live births.¹⁰ Although the location of the nodule in our patient was in the occipital region, imaging and biopsy results did not show hemorrhagic findings consistent with cephalohematoma. Management of cephalohematoma mainly is observational, as the mass slowly regresses and the accumulated blood gradually is reabsorbed.

Fungal scalp infections (tinea capitis) are common in the pediatric population. The peak incidence of this infection has been reported in children aged 3 to 7 years, with Trichophyton tonsurans and Microsporum canis as the usual causative organisms.¹¹ Clinical features of tinea capitis include scaly patches with hair loss, hair loss with black pigmented dots at the follicular openings, diffuse scalp scaling with subtle hair loss, and cervical lymphadenopathy.¹² Although less common, tinea capitis can progress to a more severe form known as a kerion, which is characterized by a tender plaque with pustules and crusting. A kerion can result in permanent scarring and alopecia if left untreated.¹² In our patient, a nodule with scaling and faint erythema was observed, but no black pigmented dots at the follicular orifices were present. Therefore, a potassium hydroxide wet mount preparation used to diagnose tinea capitis was unnecessary. Systemic oral antifungal therapy such as fluconazole or terbinafine is the standard treatment for tinea capitis.

The Diagnosis: Erythrodermic Allergic Contact Dermatitis

The worsening symptoms in our patient prompted intervention rather than observation and reassurance. Contact allergy to lanolin was suspected given the worsening presentation after the addition of Minerin, which was immediately discontinued. The patient’s family applied betamethasone cream 0.1% twice daily to severe plaques, pimecrolimus cream 1% to the face, and triamcinolone cream 0.1% to the rest of the body. At follow-up 1 week later, he experienced complete resolution of symptoms, which supported the diagnosis of erythrodermic allergic contact dermatitis (ACD).

The prevalence of ACD caused by lanolin varies among the general population from 1.2% to 6.9%.¹ Lanolin recently was named Allergen of the Year in 2023 by the American Contact Dermatitis Society.² It can be found in various commercial products, including creams, soaps, and ointments. Atopic dermatitis (AD) is a common pediatric inflammatory skin disorder that typically is treated with these products.³ In a study analyzing 533 products, up to 6% of skin care products for babies and children contained lanolin.⁴ Therefore, exposure to lanolin-containing products may be fairly common in the pediatric population.

Lanolin is a fatlike substance derived from sheep sebaceous gland secretions and extracted from sheep’s wool. Its composition varies by sheep breed, location, and extraction and purification methods. The most common allergens involve the alcoholic fraction produced by hydrolysis of lanolin.⁴ In 1996, Wolf⁵ described the “lanolin paradox,” which argued the difficulty with identifying lanolin as an allergen (similar to Fisher’s “paraben paradox”) based on 4 principles: (1) lanolin-containing topical medicaments tend to be more sensitizing than lanolin-containing cosmetics; (2) patients with ACD after applying lanolin-containing topical medicaments to damaged or ulcerated skin often can apply lanolin-containing cosmetics to normal or unaffected skin without a reaction; (3) false-negative patch test results often occur in lanolin-sensitive patients; and (4) patch testing with a single lanolin-containing agent (lanolin alcohol [30% in petrolatum]) is an unreliable and inadequate method of detecting lanolin allergy.^6,7 This theory elucidates the challenge of diagnosing contact allergies, particularly lanolin contact allergies.

Clinical features of acute ACD vary by skin type. Lighter skin types may have well-demarcated, pruritic, eczematous patches and plaques affecting the flexor surfaces. Asian patients may present with psoriasiform plaques with more well-demarcated borders and increased scaling and lichenification. In patients with darker skin types, dermatitis may manifest as papulation, lichenification, and color changes (violet, gray, or darker brown) along extensor surfaces.8 Chronic dermatitis manifests as lichenified scaly plaques. Given the diversity in dermatitis manifestation and the challenges of identifying erythema, especially in skin of color, clinicians may misidentify disease severity. These features aid in diagnosing and treating patients presenting with diffuse erythroderma and worsening eczematous patches and plaques despite use of typical topical treatments.

The differential diagnosis includes irritant contact dermatitis, AD, seborrheic dermatitis, and chronic plaque psoriasis. Negative patch testing suggests contact dermatitis based on exposure to a product. A thorough medication and personal history helps distinguish ACD from AD. Atopic dermatitis classically appears on the flexural areas, face, eyelids, and hands of patients with a personal or family history of atopy. Greasy scaly plaques on the central part of the face, eyelids, and scalp commonly are found in seborrheic dermatitis. In chronic plaque psoriasis, lesions typically are described as welldemarcated, inflamed plaques with notable scale located primarily in the scalp and diaper area in newborns and children until the age of 2 years. Our patient presented with scaly plaques throughout most of the body. The history of Minerin use over the course of 3 to 5 months and worsening skin eruptions involving a majority of the skin surface suggested continued exposure.

Patch testing assists in the diagnosis of ACD, with varying results due to manufacturing and processing inconsistencies in the composition of various substances used in the standard test sets, often making it difficult to diagnose lanolin as an allergen. According to Lee and Warshaw,6 the lack of uniformity within testing of lanolin-containing products may cause false-positive results, poor patch-test reproducibility, and loss of allergic contact response. A 2019 study utilized a combination of Amerchol L101 and lanolin alcohol to improve the diagnosis of lanolin allergy, as standard testing may not identify patients with lanolin sensitivities.1 A study with the North American Contact Dermatitis Group from 2005 to 2012 demonstrated that positive patch testing among children was the most consistent method for diagnosing ACD, and results were clinically relevant.⁹ However, the different lanolin-containing products are not standardized in patch testing, which often causes mixed reactions and does not definitely demonstrate classic positive results, even with the use of repeated open application tests.² Although there has been an emphasis on refining the standardization of the lanolin used for patch testing, lanolin contact allergy remains a predominantly clinical diagnosis.

Both AD and ACD are common pediatric skin findings, and mixed positive and neutral associations between AD and allergy to lanolin have been described in a few studies.^1,3,9,10 A history of atopy is more notable in a pediatric patient vs an adult, as sensitivities tend to subside into adulthood.⁹ Further studies and more precise testing are needed to investigate the relationship between AD and ACD.

The Diagnosis: Erythrodermic Allergic Contact Dermatitis

The worsening symptoms in our patient prompted intervention rather than observation and reassurance. Contact allergy to lanolin was suspected given the worsening presentation after the addition of Minerin, which was immediately discontinued. The patient’s family applied betamethasone cream 0.1% twice daily to severe plaques, pimecrolimus cream 1% to the face, and triamcinolone cream 0.1% to the rest of the body. At follow-up 1 week later, he experienced complete resolution of symptoms, which supported the diagnosis of erythrodermic allergic contact dermatitis (ACD).

The prevalence of ACD caused by lanolin varies among the general population from 1.2% to 6.9%.¹ Lanolin recently was named Allergen of the Year in 2023 by the American Contact Dermatitis Society.² It can be found in various commercial products, including creams, soaps, and ointments. Atopic dermatitis (AD) is a common pediatric inflammatory skin disorder that typically is treated with these products.³ In a study analyzing 533 products, up to 6% of skin care products for babies and children contained lanolin.⁴ Therefore, exposure to lanolin-containing products may be fairly common in the pediatric population.

Lanolin is a fatlike substance derived from sheep sebaceous gland secretions and extracted from sheep’s wool. Its composition varies by sheep breed, location, and extraction and purification methods. The most common allergens involve the alcoholic fraction produced by hydrolysis of lanolin.⁴ In 1996, Wolf⁵ described the “lanolin paradox,” which argued the difficulty with identifying lanolin as an allergen (similar to Fisher’s “paraben paradox”) based on 4 principles: (1) lanolin-containing topical medicaments tend to be more sensitizing than lanolin-containing cosmetics; (2) patients with ACD after applying lanolin-containing topical medicaments to damaged or ulcerated skin often can apply lanolin-containing cosmetics to normal or unaffected skin without a reaction; (3) false-negative patch test results often occur in lanolin-sensitive patients; and (4) patch testing with a single lanolin-containing agent (lanolin alcohol [30% in petrolatum]) is an unreliable and inadequate method of detecting lanolin allergy.^6,7 This theory elucidates the challenge of diagnosing contact allergies, particularly lanolin contact allergies.

Clinical features of acute ACD vary by skin type. Lighter skin types may have well-demarcated, pruritic, eczematous patches and plaques affecting the flexor surfaces. Asian patients may present with psoriasiform plaques with more well-demarcated borders and increased scaling and lichenification. In patients with darker skin types, dermatitis may manifest as papulation, lichenification, and color changes (violet, gray, or darker brown) along extensor surfaces.8 Chronic dermatitis manifests as lichenified scaly plaques. Given the diversity in dermatitis manifestation and the challenges of identifying erythema, especially in skin of color, clinicians may misidentify disease severity. These features aid in diagnosing and treating patients presenting with diffuse erythroderma and worsening eczematous patches and plaques despite use of typical topical treatments.

The differential diagnosis includes irritant contact dermatitis, AD, seborrheic dermatitis, and chronic plaque psoriasis. Negative patch testing suggests contact dermatitis based on exposure to a product. A thorough medication and personal history helps distinguish ACD from AD. Atopic dermatitis classically appears on the flexural areas, face, eyelids, and hands of patients with a personal or family history of atopy. Greasy scaly plaques on the central part of the face, eyelids, and scalp commonly are found in seborrheic dermatitis. In chronic plaque psoriasis, lesions typically are described as welldemarcated, inflamed plaques with notable scale located primarily in the scalp and diaper area in newborns and children until the age of 2 years. Our patient presented with scaly plaques throughout most of the body. The history of Minerin use over the course of 3 to 5 months and worsening skin eruptions involving a majority of the skin surface suggested continued exposure.

Patch testing assists in the diagnosis of ACD, with varying results due to manufacturing and processing inconsistencies in the composition of various substances used in the standard test sets, often making it difficult to diagnose lanolin as an allergen. According to Lee and Warshaw,6 the lack of uniformity within testing of lanolin-containing products may cause false-positive results, poor patch-test reproducibility, and loss of allergic contact response. A 2019 study utilized a combination of Amerchol L101 and lanolin alcohol to improve the diagnosis of lanolin allergy, as standard testing may not identify patients with lanolin sensitivities.1 A study with the North American Contact Dermatitis Group from 2005 to 2012 demonstrated that positive patch testing among children was the most consistent method for diagnosing ACD, and results were clinically relevant.⁹ However, the different lanolin-containing products are not standardized in patch testing, which often causes mixed reactions and does not definitely demonstrate classic positive results, even with the use of repeated open application tests.² Although there has been an emphasis on refining the standardization of the lanolin used for patch testing, lanolin contact allergy remains a predominantly clinical diagnosis.

Both AD and ACD are common pediatric skin findings, and mixed positive and neutral associations between AD and allergy to lanolin have been described in a few studies.^1,3,9,10 A history of atopy is more notable in a pediatric patient vs an adult, as sensitivities tend to subside into adulthood.⁹ Further studies and more precise testing are needed to investigate the relationship between AD and ACD.

The Diagnosis: Erythrodermic Allergic Contact Dermatitis

The worsening symptoms in our patient prompted intervention rather than observation and reassurance. Contact allergy to lanolin was suspected given the worsening presentation after the addition of Minerin, which was immediately discontinued. The patient’s family applied betamethasone cream 0.1% twice daily to severe plaques, pimecrolimus cream 1% to the face, and triamcinolone cream 0.1% to the rest of the body. At follow-up 1 week later, he experienced complete resolution of symptoms, which supported the diagnosis of erythrodermic allergic contact dermatitis (ACD).

The prevalence of ACD caused by lanolin varies among the general population from 1.2% to 6.9%.¹ Lanolin recently was named Allergen of the Year in 2023 by the American Contact Dermatitis Society.² It can be found in various commercial products, including creams, soaps, and ointments. Atopic dermatitis (AD) is a common pediatric inflammatory skin disorder that typically is treated with these products.³ In a study analyzing 533 products, up to 6% of skin care products for babies and children contained lanolin.⁴ Therefore, exposure to lanolin-containing products may be fairly common in the pediatric population.

Lanolin is a fatlike substance derived from sheep sebaceous gland secretions and extracted from sheep’s wool. Its composition varies by sheep breed, location, and extraction and purification methods. The most common allergens involve the alcoholic fraction produced by hydrolysis of lanolin.⁴ In 1996, Wolf⁵ described the “lanolin paradox,” which argued the difficulty with identifying lanolin as an allergen (similar to Fisher’s “paraben paradox”) based on 4 principles: (1) lanolin-containing topical medicaments tend to be more sensitizing than lanolin-containing cosmetics; (2) patients with ACD after applying lanolin-containing topical medicaments to damaged or ulcerated skin often can apply lanolin-containing cosmetics to normal or unaffected skin without a reaction; (3) false-negative patch test results often occur in lanolin-sensitive patients; and (4) patch testing with a single lanolin-containing agent (lanolin alcohol [30% in petrolatum]) is an unreliable and inadequate method of detecting lanolin allergy.^6,7 This theory elucidates the challenge of diagnosing contact allergies, particularly lanolin contact allergies.

Clinical features of acute ACD vary by skin type. Lighter skin types may have well-demarcated, pruritic, eczematous patches and plaques affecting the flexor surfaces. Asian patients may present with psoriasiform plaques with more well-demarcated borders and increased scaling and lichenification. In patients with darker skin types, dermatitis may manifest as papulation, lichenification, and color changes (violet, gray, or darker brown) along extensor surfaces.8 Chronic dermatitis manifests as lichenified scaly plaques. Given the diversity in dermatitis manifestation and the challenges of identifying erythema, especially in skin of color, clinicians may misidentify disease severity. These features aid in diagnosing and treating patients presenting with diffuse erythroderma and worsening eczematous patches and plaques despite use of typical topical treatments.

The differential diagnosis includes irritant contact dermatitis, AD, seborrheic dermatitis, and chronic plaque psoriasis. Negative patch testing suggests contact dermatitis based on exposure to a product. A thorough medication and personal history helps distinguish ACD from AD. Atopic dermatitis classically appears on the flexural areas, face, eyelids, and hands of patients with a personal or family history of atopy. Greasy scaly plaques on the central part of the face, eyelids, and scalp commonly are found in seborrheic dermatitis. In chronic plaque psoriasis, lesions typically are described as welldemarcated, inflamed plaques with notable scale located primarily in the scalp and diaper area in newborns and children until the age of 2 years. Our patient presented with scaly plaques throughout most of the body. The history of Minerin use over the course of 3 to 5 months and worsening skin eruptions involving a majority of the skin surface suggested continued exposure.

Patch testing assists in the diagnosis of ACD, with varying results due to manufacturing and processing inconsistencies in the composition of various substances used in the standard test sets, often making it difficult to diagnose lanolin as an allergen. According to Lee and Warshaw,6 the lack of uniformity within testing of lanolin-containing products may cause false-positive results, poor patch-test reproducibility, and loss of allergic contact response. A 2019 study utilized a combination of Amerchol L101 and lanolin alcohol to improve the diagnosis of lanolin allergy, as standard testing may not identify patients with lanolin sensitivities.1 A study with the North American Contact Dermatitis Group from 2005 to 2012 demonstrated that positive patch testing among children was the most consistent method for diagnosing ACD, and results were clinically relevant.⁹ However, the different lanolin-containing products are not standardized in patch testing, which often causes mixed reactions and does not definitely demonstrate classic positive results, even with the use of repeated open application tests.² Although there has been an emphasis on refining the standardization of the lanolin used for patch testing, lanolin contact allergy remains a predominantly clinical diagnosis.

Both AD and ACD are common pediatric skin findings, and mixed positive and neutral associations between AD and allergy to lanolin have been described in a few studies.^1,3,9,10 A history of atopy is more notable in a pediatric patient vs an adult, as sensitivities tend to subside into adulthood.⁹ Further studies and more precise testing are needed to investigate the relationship between AD and ACD.

The Diagnosis: Hypertrophic Lichen Planus

Two biopsies from the left lateral foot revealed hyperkeratosis, wedge-shaped hypergranulosis, irregular acanthosis, and a bandlike lymphocytic infiltrate in the superficial dermis with a classic sawtooth pattern of the rete ridges (Figure 1). Based on the clinical findings and histopathology, the patient was diagnosed with hypertrophic lichen planus (LP) and was treated with clobetasol ointment 0.05%, which resulted in progression of the symptoms. She experienced notable improvement 3 months after adding methotrexate 12.5 mg weekly (Figure 2).

Medina_1.jpg

Lichen planus is an idiopathic chronic inflammatory condition of the skin and mucous membranes that classically manifests as pruritic violaceous papules and plaques, which commonly are found on the wrists, lower back, and ankles.¹ The most common variants of LP are hypertrophic, linear, mucosal, actinic, follicular, pigmented, annular, atrophic, and guttate.² The clinical presentation and biopsy results in our patient were consistent with the hypertrophic variant of LP, which is a chronic condition that most often manifests on the lower legs, especially around the ankles, as hyperkeratotic papules, plaques, and nodules.^2,3 The exact pathophysiology of hypertrophic LP is unknown, but there is evidence that the immune system plays a role in its development and that the Koebner phenomenon may contribute to its exacerbation.⁴ There is a well-known association between LP and hepatitis. Patients with chronic LP may develop squamous cell carcinoma.⁴ The variants of LP can overlap and do not exist independent of one another. Recognizing the overlap in these variants allows for earlier diagnosis and therapeutic intervention of the disease process to limit disease progression and patient clinic visits and to improve patient quality of life.

CT113004010_e_Fig2_AB.jpg

The differential diagnosis for hyperkeratotic plaques of the feet and ankles can be broad and may include keratosis lichenoides chronica, palmoplantar keratoderma, palmoplantar psoriasis, or lichen amyloidosis. These conditions are classified based on various criteria that include extent of disease manifestations, morphology of palmoplantar skin involvement, inheritance patterns, and molecular pathogenesis.⁵ Keratosis lichenoides chronica is a rare dermatosis that presents as a distinctive seborrheic dermatitis–like facial eruption. The facial eruption is accompanied by violaceous papular and nodular lesions that appear on the extremities and trunk, typically arranged in a linear or reticular pattern.⁶ Palmoplantar keratoderma represents a group of acquired and hereditary conditions that are characterized by excessive thickening of the palms and soles.⁵ Palmoplantar psoriasis is a variant of psoriasis that affects the palms and soles and can manifest as hyperkeratosis, pustular, or mixed morphology.⁷ Lichen amyloidosis is a subtype of primary localized cutaneous amyloidosis that manifests as multiple pruritic, firm, hyperpigmented, hyperkeratotic papules on the shins that later coalesce in a rippled pattern.^8,9

The first-line treatment for hypertrophic LP is topical corticosteroids. Alternative therapies include mycophenolate mofetil, acitretin, and intralesional corticosteroid injections.⁴ Treatment is similar for all of the LP variants.

The Diagnosis: Hypertrophic Lichen Planus

Two biopsies from the left lateral foot revealed hyperkeratosis, wedge-shaped hypergranulosis, irregular acanthosis, and a bandlike lymphocytic infiltrate in the superficial dermis with a classic sawtooth pattern of the rete ridges (Figure 1). Based on the clinical findings and histopathology, the patient was diagnosed with hypertrophic lichen planus (LP) and was treated with clobetasol ointment 0.05%, which resulted in progression of the symptoms. She experienced notable improvement 3 months after adding methotrexate 12.5 mg weekly (Figure 2).

Medina_1.jpg

Lichen planus is an idiopathic chronic inflammatory condition of the skin and mucous membranes that classically manifests as pruritic violaceous papules and plaques, which commonly are found on the wrists, lower back, and ankles.¹ The most common variants of LP are hypertrophic, linear, mucosal, actinic, follicular, pigmented, annular, atrophic, and guttate.² The clinical presentation and biopsy results in our patient were consistent with the hypertrophic variant of LP, which is a chronic condition that most often manifests on the lower legs, especially around the ankles, as hyperkeratotic papules, plaques, and nodules.^2,3 The exact pathophysiology of hypertrophic LP is unknown, but there is evidence that the immune system plays a role in its development and that the Koebner phenomenon may contribute to its exacerbation.⁴ There is a well-known association between LP and hepatitis. Patients with chronic LP may develop squamous cell carcinoma.⁴ The variants of LP can overlap and do not exist independent of one another. Recognizing the overlap in these variants allows for earlier diagnosis and therapeutic intervention of the disease process to limit disease progression and patient clinic visits and to improve patient quality of life.

CT113004010_e_Fig2_AB.jpg

The differential diagnosis for hyperkeratotic plaques of the feet and ankles can be broad and may include keratosis lichenoides chronica, palmoplantar keratoderma, palmoplantar psoriasis, or lichen amyloidosis. These conditions are classified based on various criteria that include extent of disease manifestations, morphology of palmoplantar skin involvement, inheritance patterns, and molecular pathogenesis.⁵ Keratosis lichenoides chronica is a rare dermatosis that presents as a distinctive seborrheic dermatitis–like facial eruption. The facial eruption is accompanied by violaceous papular and nodular lesions that appear on the extremities and trunk, typically arranged in a linear or reticular pattern.⁶ Palmoplantar keratoderma represents a group of acquired and hereditary conditions that are characterized by excessive thickening of the palms and soles.⁵ Palmoplantar psoriasis is a variant of psoriasis that affects the palms and soles and can manifest as hyperkeratosis, pustular, or mixed morphology.⁷ Lichen amyloidosis is a subtype of primary localized cutaneous amyloidosis that manifests as multiple pruritic, firm, hyperpigmented, hyperkeratotic papules on the shins that later coalesce in a rippled pattern.^8,9

The first-line treatment for hypertrophic LP is topical corticosteroids. Alternative therapies include mycophenolate mofetil, acitretin, and intralesional corticosteroid injections.⁴ Treatment is similar for all of the LP variants.

The Diagnosis: Hypertrophic Lichen Planus

Two biopsies from the left lateral foot revealed hyperkeratosis, wedge-shaped hypergranulosis, irregular acanthosis, and a bandlike lymphocytic infiltrate in the superficial dermis with a classic sawtooth pattern of the rete ridges (Figure 1). Based on the clinical findings and histopathology, the patient was diagnosed with hypertrophic lichen planus (LP) and was treated with clobetasol ointment 0.05%, which resulted in progression of the symptoms. She experienced notable improvement 3 months after adding methotrexate 12.5 mg weekly (Figure 2).

Medina_1.jpg

Lichen planus is an idiopathic chronic inflammatory condition of the skin and mucous membranes that classically manifests as pruritic violaceous papules and plaques, which commonly are found on the wrists, lower back, and ankles.¹ The most common variants of LP are hypertrophic, linear, mucosal, actinic, follicular, pigmented, annular, atrophic, and guttate.² The clinical presentation and biopsy results in our patient were consistent with the hypertrophic variant of LP, which is a chronic condition that most often manifests on the lower legs, especially around the ankles, as hyperkeratotic papules, plaques, and nodules.^2,3 The exact pathophysiology of hypertrophic LP is unknown, but there is evidence that the immune system plays a role in its development and that the Koebner phenomenon may contribute to its exacerbation.⁴ There is a well-known association between LP and hepatitis. Patients with chronic LP may develop squamous cell carcinoma.⁴ The variants of LP can overlap and do not exist independent of one another. Recognizing the overlap in these variants allows for earlier diagnosis and therapeutic intervention of the disease process to limit disease progression and patient clinic visits and to improve patient quality of life.

CT113004010_e_Fig2_AB.jpg

The differential diagnosis for hyperkeratotic plaques of the feet and ankles can be broad and may include keratosis lichenoides chronica, palmoplantar keratoderma, palmoplantar psoriasis, or lichen amyloidosis. These conditions are classified based on various criteria that include extent of disease manifestations, morphology of palmoplantar skin involvement, inheritance patterns, and molecular pathogenesis.⁵ Keratosis lichenoides chronica is a rare dermatosis that presents as a distinctive seborrheic dermatitis–like facial eruption. The facial eruption is accompanied by violaceous papular and nodular lesions that appear on the extremities and trunk, typically arranged in a linear or reticular pattern.⁶ Palmoplantar keratoderma represents a group of acquired and hereditary conditions that are characterized by excessive thickening of the palms and soles.⁵ Palmoplantar psoriasis is a variant of psoriasis that affects the palms and soles and can manifest as hyperkeratosis, pustular, or mixed morphology.⁷ Lichen amyloidosis is a subtype of primary localized cutaneous amyloidosis that manifests as multiple pruritic, firm, hyperpigmented, hyperkeratotic papules on the shins that later coalesce in a rippled pattern.^8,9

The first-line treatment for hypertrophic LP is topical corticosteroids. Alternative therapies include mycophenolate mofetil, acitretin, and intralesional corticosteroid injections.⁴ Treatment is similar for all of the LP variants.

The Diagnosis: Erythema Migrans

The patient was clinically diagnosed with erythema migrans. He did not recall a tick bite but spent a lot of time outdoors. He was treated with 10 days of doxycycline 100 mg twice daily with complete resolution of the rash.

Lyme disease is a spirochete infection caused by the Borrelia burgdorferi sensu lato species complex and transmitted by the Ixodidae tick family. It is the most common tick-borne disease in the United States and mostly is reported in the northeastern and upper midwestern states during the warmer seasons, but it is prevalent worldwide. In geographic areas where Lyme disease is common, the incidence is approximately 40 cases per 100,000 individuals.¹ Our patient resided in coastal South Carolina. Lyme disease is more commonly reported in White individuals. The skin lesions may be more difficult to discern and diagnose in patients with darker skin types, leading to delayed diagnosis and treatment.^2,3

Patients may be diagnosed with early localized, early disseminated, or late Lyme disease. Erythema migrans is the early localized form of the disease and is classically described as an erythematous targetlike plaque with raised borders arising at the site of the tick bite 1 to 2 weeks later.⁴ However, many patients simply have a homogeneous erythematous plaque with raised advancing borders ranging in size from 5 to 68 cm.⁵ In a 2022 study of 69 patients with suspected Lyme disease, only 35 (50.7%) were determined to truly have acute Lyme disease.⁶ Of them, only 2 (5.7%) had the classic ringwithin- a-ring pattern. Most plaques were uniform, pink, oval-shaped lesions with well-demarcated borders.⁶

The rash may present with a burning sensation, or patients may experience no symptoms at all, which can lead to delayed diagnosis and progression to late disease. Patients may develop malaise, fever, headache, body aches, or joint pain. Early disseminated disease manifests similarly. Patients with disseminated disease also may develop more serious complications, including lymphadenopathy; cranial nerve palsies; ocular involvement; meningitis; or cardiac abnormalities such as myocarditis, pericarditis, or arrhythmia. Late disease most often causes arthritis of the large joints, though it also can have cardiac or neurologic manifestations. Some patients with chronic disease—the majority of whom were diagnosed in Europe—may develop acrodermatitis chronica atrophicans with edematous blue-red plaques that become atrophic and hyperpigmented fibrotic plaques over the course of years.

Allergic contact dermatitis to a plant more likely would cause itchy or painful, oozy, weepy, vesicular lesions arranged in a linear pattern. A dermatophyte infection likely would cause a scaly eruption. Although our patient presented with a sharply demarcated, raised, erythematous lesion, the distribution did not follow normal clothing lines and would be unusual for a photosensitive drug eruption. Cellulitis likely would be associated with tenderness or warmth to the touch. Finally, southern tick-associated rash illness, which is associated with Amblyomma americanum (lone star tick) bites, may appear with a similar rash but few systemic symptoms. It also can be treated with tetracycline antibiotics.⁷

Our case in South Carolina demonstrates the importance of keeping Lyme disease in the differential. Clinicians should remember to ask patients about their travel history. In endemic areas, patients with erythema migrans can be started on treatment without waiting for serology. Patients with early Lyme disease may or may not have positive serologies at the time of presentation.⁶ Guidelines for the treatment of Lyme disease have been revised in recent years to decrease patient antibiotic exposure by reducing the number of days of antibiotic therapy.⁸ A recent randomized controlled trial found no significant difference in recurrence for patients treated with 7 days of doxycycline compared with 14 days.⁹ We typically prescribe a 10-day course of doxycycline, which also is adequate for concurrent rickettsial disease. Patients who develop malarialike symptoms should be evaluated for babesiosis, which is treated with clindamycin.

The Diagnosis: Erythema Migrans

The patient was clinically diagnosed with erythema migrans. He did not recall a tick bite but spent a lot of time outdoors. He was treated with 10 days of doxycycline 100 mg twice daily with complete resolution of the rash.

Lyme disease is a spirochete infection caused by the Borrelia burgdorferi sensu lato species complex and transmitted by the Ixodidae tick family. It is the most common tick-borne disease in the United States and mostly is reported in the northeastern and upper midwestern states during the warmer seasons, but it is prevalent worldwide. In geographic areas where Lyme disease is common, the incidence is approximately 40 cases per 100,000 individuals.¹ Our patient resided in coastal South Carolina. Lyme disease is more commonly reported in White individuals. The skin lesions may be more difficult to discern and diagnose in patients with darker skin types, leading to delayed diagnosis and treatment.^2,3

Patients may be diagnosed with early localized, early disseminated, or late Lyme disease. Erythema migrans is the early localized form of the disease and is classically described as an erythematous targetlike plaque with raised borders arising at the site of the tick bite 1 to 2 weeks later.⁴ However, many patients simply have a homogeneous erythematous plaque with raised advancing borders ranging in size from 5 to 68 cm.⁵ In a 2022 study of 69 patients with suspected Lyme disease, only 35 (50.7%) were determined to truly have acute Lyme disease.⁶ Of them, only 2 (5.7%) had the classic ringwithin- a-ring pattern. Most plaques were uniform, pink, oval-shaped lesions with well-demarcated borders.⁶

The rash may present with a burning sensation, or patients may experience no symptoms at all, which can lead to delayed diagnosis and progression to late disease. Patients may develop malaise, fever, headache, body aches, or joint pain. Early disseminated disease manifests similarly. Patients with disseminated disease also may develop more serious complications, including lymphadenopathy; cranial nerve palsies; ocular involvement; meningitis; or cardiac abnormalities such as myocarditis, pericarditis, or arrhythmia. Late disease most often causes arthritis of the large joints, though it also can have cardiac or neurologic manifestations. Some patients with chronic disease—the majority of whom were diagnosed in Europe—may develop acrodermatitis chronica atrophicans with edematous blue-red plaques that become atrophic and hyperpigmented fibrotic plaques over the course of years.

Allergic contact dermatitis to a plant more likely would cause itchy or painful, oozy, weepy, vesicular lesions arranged in a linear pattern. A dermatophyte infection likely would cause a scaly eruption. Although our patient presented with a sharply demarcated, raised, erythematous lesion, the distribution did not follow normal clothing lines and would be unusual for a photosensitive drug eruption. Cellulitis likely would be associated with tenderness or warmth to the touch. Finally, southern tick-associated rash illness, which is associated with Amblyomma americanum (lone star tick) bites, may appear with a similar rash but few systemic symptoms. It also can be treated with tetracycline antibiotics.⁷

Our case in South Carolina demonstrates the importance of keeping Lyme disease in the differential. Clinicians should remember to ask patients about their travel history. In endemic areas, patients with erythema migrans can be started on treatment without waiting for serology. Patients with early Lyme disease may or may not have positive serologies at the time of presentation.⁶ Guidelines for the treatment of Lyme disease have been revised in recent years to decrease patient antibiotic exposure by reducing the number of days of antibiotic therapy.⁸ A recent randomized controlled trial found no significant difference in recurrence for patients treated with 7 days of doxycycline compared with 14 days.⁹ We typically prescribe a 10-day course of doxycycline, which also is adequate for concurrent rickettsial disease. Patients who develop malarialike symptoms should be evaluated for babesiosis, which is treated with clindamycin.

The Diagnosis: Erythema Migrans

The patient was clinically diagnosed with erythema migrans. He did not recall a tick bite but spent a lot of time outdoors. He was treated with 10 days of doxycycline 100 mg twice daily with complete resolution of the rash.

Lyme disease is a spirochete infection caused by the Borrelia burgdorferi sensu lato species complex and transmitted by the Ixodidae tick family. It is the most common tick-borne disease in the United States and mostly is reported in the northeastern and upper midwestern states during the warmer seasons, but it is prevalent worldwide. In geographic areas where Lyme disease is common, the incidence is approximately 40 cases per 100,000 individuals.¹ Our patient resided in coastal South Carolina. Lyme disease is more commonly reported in White individuals. The skin lesions may be more difficult to discern and diagnose in patients with darker skin types, leading to delayed diagnosis and treatment.^2,3

Patients may be diagnosed with early localized, early disseminated, or late Lyme disease. Erythema migrans is the early localized form of the disease and is classically described as an erythematous targetlike plaque with raised borders arising at the site of the tick bite 1 to 2 weeks later.⁴ However, many patients simply have a homogeneous erythematous plaque with raised advancing borders ranging in size from 5 to 68 cm.⁵ In a 2022 study of 69 patients with suspected Lyme disease, only 35 (50.7%) were determined to truly have acute Lyme disease.⁶ Of them, only 2 (5.7%) had the classic ringwithin- a-ring pattern. Most plaques were uniform, pink, oval-shaped lesions with well-demarcated borders.⁶

The rash may present with a burning sensation, or patients may experience no symptoms at all, which can lead to delayed diagnosis and progression to late disease. Patients may develop malaise, fever, headache, body aches, or joint pain. Early disseminated disease manifests similarly. Patients with disseminated disease also may develop more serious complications, including lymphadenopathy; cranial nerve palsies; ocular involvement; meningitis; or cardiac abnormalities such as myocarditis, pericarditis, or arrhythmia. Late disease most often causes arthritis of the large joints, though it also can have cardiac or neurologic manifestations. Some patients with chronic disease—the majority of whom were diagnosed in Europe—may develop acrodermatitis chronica atrophicans with edematous blue-red plaques that become atrophic and hyperpigmented fibrotic plaques over the course of years.

Allergic contact dermatitis to a plant more likely would cause itchy or painful, oozy, weepy, vesicular lesions arranged in a linear pattern. A dermatophyte infection likely would cause a scaly eruption. Although our patient presented with a sharply demarcated, raised, erythematous lesion, the distribution did not follow normal clothing lines and would be unusual for a photosensitive drug eruption. Cellulitis likely would be associated with tenderness or warmth to the touch. Finally, southern tick-associated rash illness, which is associated with Amblyomma americanum (lone star tick) bites, may appear with a similar rash but few systemic symptoms. It also can be treated with tetracycline antibiotics.⁷

Our case in South Carolina demonstrates the importance of keeping Lyme disease in the differential. Clinicians should remember to ask patients about their travel history. In endemic areas, patients with erythema migrans can be started on treatment without waiting for serology. Patients with early Lyme disease may or may not have positive serologies at the time of presentation.⁶ Guidelines for the treatment of Lyme disease have been revised in recent years to decrease patient antibiotic exposure by reducing the number of days of antibiotic therapy.⁸ A recent randomized controlled trial found no significant difference in recurrence for patients treated with 7 days of doxycycline compared with 14 days.⁹ We typically prescribe a 10-day course of doxycycline, which also is adequate for concurrent rickettsial disease. Patients who develop malarialike symptoms should be evaluated for babesiosis, which is treated with clindamycin.

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

Cutaneous plasmacytoma initially was suspected because of the patient’s history of monoclonal gammopathy as well as angiosarcoma due to the purpuric vascular appearance of the lesions. However, histopathology revealed a pleomorphic cellular dermal infiltrate characterized by atypical cells with mediumlarge nuclei, fine chromatin, and small nucleoli; the cells also had little cytoplasm (Figure). The infiltrate did not involve the epidermis but extended into the subcutaneous tissue. Immunohistochemistry revealed that the cells were positive for CD45, CD43, CD4, CD7, CD56, CD123, CD33, T-cell leukemia/lymphoma protein 1, and CD68. The cells were negative for CD2, CD3, CD5, CD8, T-cell intracellular antigen 1, CD13, CD15, CD19, CD20, CD21, CD23, cyclin D1, Bcl-2, Bcl-6, CD10, PAX5, MUM1, lysozyme, myeloperoxidase, perforin, granzyme B, CD57, CD34, CD117, terminal deoxynucleotidyl transferase, activin receptorlike kinase 1 βF1, Epstein-Barr virus– encoded small RNA, CD30, CD163, and pancytokeratin. Thus, the clinical and histopathologic findings led to a diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare and aggressive hematologic malignancy.

CT113003025_e_FigAB.jpg

Blastic plasmacytoid dendritic cell neoplasm affects males older than 60 years.¹ It is characterized by the clonal proliferation of precursor plasmacytoid dendritic cells—otherwise known as professional type I interferonproducing cells or plasmacytoid monocytes—of myeloid origin. Plasmacytoid dendritic cells have been renamed on several occasions, reflecting uncertainties of their histogenesis. The diagnosis of BPDCN requires a biopsy showing the morphology of plasmacytoid dendritic blast cells and immunophenotypic criteria established by either immunohistochemistry or flow cytometry.^2,3 Tumor cells morphologically show an immature blastic appearance, and the diagnosis rests upon the demonstration of CD4 and CD56, together with markers more restricted to plasmacytoid dendritic cells (eg, BDCA-2, CD123, T-cell leukemia/lymphoma protein 1, CD2AP, BCL11A) and negativity for lymphoid and myeloid lineage–associated antigens.^1,4

Blastic plasmacytoid dendritic cell neoplasms account for less than 1% of all hematopoietic neoplasms. Cutaneous lesions occur in 64% of patients with the disease and often are the reason patients seek medical care.⁵ Clinical findings include numerous erythematous and violaceous papules, nodules, and plaques that resemble purpura or vasculitis. Cutaneous lesions can vary in size from a few millimeters to 10 cm and vary in color. Moreover, patients often present with bruiselike patches, disseminated lesions, or mucosal lesions.¹ Extracutaneous involvement includes lymphadenopathy, splenomegaly, and cytopenia caused by bone marrow infiltration, which may be present at diagnosis or during disease progression. Bone marrow involvement often is present with thrombocytopenia, anemia, and neutropenia. One-third of patients with BPDCN have central nervous system involvement and no disease relapse.⁶ Other affected sites include the liver, lungs, tonsils, soft tissues, and eyes. Patients with BPDCN may present with a history of myeloid neoplasms, such as acute/chronic myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome.⁴ Our case highlights the importance of skin biopsy for making the correct diagnosis, as BPDCN manifests with cutaneous lesions that are nonspecific for neoplastic or nonneoplastic etiologies.

Given the aggressive nature of BPDCN, along with its potential for acute leukemic transformation, treatment has been challenging due to both poor response rates and lack of consensus and treatment strategies. Historically, patients who have received high-dose acute leukemia–based chemotherapy followed by an allogeneic stem cell transplant during the first remission appeared to have the best outcomes.⁷ Conventional treatments have included surgical excision with radiation and various leukemia-based chemotherapy regimens, with hyper- CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone-methotrexate, and cytarabine) being the most commonly used regimen.^7,8 Venetoclax, a B-cell lymphoma 2 protein inhibitor, has shown promise when used in combination with hyper-CVAD. For older patients who may not tolerate aggressive chemotherapy, hypomethylating agents are preferred for their tolerability. Although tagraxofusp, a CD123-directed cytotoxin, has been utilized, Sapienza et al⁹ demonstrated an association with capillary leak syndrome.

Leukemia cutis is characterized by infiltration of the skin by malignant leukocytes, often associated with a prior diagnosis of systemic leukemia or myelodysplasia. Extramedullary accumulation of leukemic cells typically is referred to as myeloid sarcoma, while leukemia cutis serves as a general term for specific skin involvement.¹⁰ In rare instances, cutaneous lesions may manifest as the initial sign of systemic disease.

Cutaneous T-cell lymphomas comprise a diverse group of non-Hodgkin lymphomas that manifest as malignant monoclonal T-lymphocyte infiltration in the skin. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T-cell lymphomas are among the key subtypes. Histologically, differentiating these conditions from benign inflammatory disorders can be challenging due to subtle features such as haloed lymphocytes, epidermotropism, and Pautrier microabscesses seen in mycosis fungoides.¹¹

Multiple myeloma involves monoclonal plasma cell proliferation, primarily affecting bone and bone marrow. Extramedullary plasmacytomas can occur outside these sites through hematogenous spread or adjacent infiltration, while metastatic plasmacytomas result from metastasis. Cutaneous plasmacytomas may arise from hematogenous dissemination or infiltration from neighboring structures.¹²

Extranodal natural killer/T-cell lymphoma, nasal type, manifests as aggressive mid-facial necrotizing lesions with extranodal involvement, notably in the nasal/paranasal area. These lesions can cause local destruction of cartilage, bone, and soft tissues and may progress through stages or arise de novo. Diagnostic challenges arise from the historical variety of terms used to describe extranodal natural killer/T-cell lymphoma, including midline lethal granuloma and lymphomatoid granulomatosis.¹³

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

Cutaneous plasmacytoma initially was suspected because of the patient’s history of monoclonal gammopathy as well as angiosarcoma due to the purpuric vascular appearance of the lesions. However, histopathology revealed a pleomorphic cellular dermal infiltrate characterized by atypical cells with mediumlarge nuclei, fine chromatin, and small nucleoli; the cells also had little cytoplasm (Figure). The infiltrate did not involve the epidermis but extended into the subcutaneous tissue. Immunohistochemistry revealed that the cells were positive for CD45, CD43, CD4, CD7, CD56, CD123, CD33, T-cell leukemia/lymphoma protein 1, and CD68. The cells were negative for CD2, CD3, CD5, CD8, T-cell intracellular antigen 1, CD13, CD15, CD19, CD20, CD21, CD23, cyclin D1, Bcl-2, Bcl-6, CD10, PAX5, MUM1, lysozyme, myeloperoxidase, perforin, granzyme B, CD57, CD34, CD117, terminal deoxynucleotidyl transferase, activin receptorlike kinase 1 βF1, Epstein-Barr virus– encoded small RNA, CD30, CD163, and pancytokeratin. Thus, the clinical and histopathologic findings led to a diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare and aggressive hematologic malignancy.

CT113003025_e_FigAB.jpg

Blastic plasmacytoid dendritic cell neoplasm affects males older than 60 years.¹ It is characterized by the clonal proliferation of precursor plasmacytoid dendritic cells—otherwise known as professional type I interferonproducing cells or plasmacytoid monocytes—of myeloid origin. Plasmacytoid dendritic cells have been renamed on several occasions, reflecting uncertainties of their histogenesis. The diagnosis of BPDCN requires a biopsy showing the morphology of plasmacytoid dendritic blast cells and immunophenotypic criteria established by either immunohistochemistry or flow cytometry.^2,3 Tumor cells morphologically show an immature blastic appearance, and the diagnosis rests upon the demonstration of CD4 and CD56, together with markers more restricted to plasmacytoid dendritic cells (eg, BDCA-2, CD123, T-cell leukemia/lymphoma protein 1, CD2AP, BCL11A) and negativity for lymphoid and myeloid lineage–associated antigens.^1,4

Blastic plasmacytoid dendritic cell neoplasms account for less than 1% of all hematopoietic neoplasms. Cutaneous lesions occur in 64% of patients with the disease and often are the reason patients seek medical care.⁵ Clinical findings include numerous erythematous and violaceous papules, nodules, and plaques that resemble purpura or vasculitis. Cutaneous lesions can vary in size from a few millimeters to 10 cm and vary in color. Moreover, patients often present with bruiselike patches, disseminated lesions, or mucosal lesions.¹ Extracutaneous involvement includes lymphadenopathy, splenomegaly, and cytopenia caused by bone marrow infiltration, which may be present at diagnosis or during disease progression. Bone marrow involvement often is present with thrombocytopenia, anemia, and neutropenia. One-third of patients with BPDCN have central nervous system involvement and no disease relapse.⁶ Other affected sites include the liver, lungs, tonsils, soft tissues, and eyes. Patients with BPDCN may present with a history of myeloid neoplasms, such as acute/chronic myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome.⁴ Our case highlights the importance of skin biopsy for making the correct diagnosis, as BPDCN manifests with cutaneous lesions that are nonspecific for neoplastic or nonneoplastic etiologies.

Given the aggressive nature of BPDCN, along with its potential for acute leukemic transformation, treatment has been challenging due to both poor response rates and lack of consensus and treatment strategies. Historically, patients who have received high-dose acute leukemia–based chemotherapy followed by an allogeneic stem cell transplant during the first remission appeared to have the best outcomes.⁷ Conventional treatments have included surgical excision with radiation and various leukemia-based chemotherapy regimens, with hyper- CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone-methotrexate, and cytarabine) being the most commonly used regimen.^7,8 Venetoclax, a B-cell lymphoma 2 protein inhibitor, has shown promise when used in combination with hyper-CVAD. For older patients who may not tolerate aggressive chemotherapy, hypomethylating agents are preferred for their tolerability. Although tagraxofusp, a CD123-directed cytotoxin, has been utilized, Sapienza et al⁹ demonstrated an association with capillary leak syndrome.

Leukemia cutis is characterized by infiltration of the skin by malignant leukocytes, often associated with a prior diagnosis of systemic leukemia or myelodysplasia. Extramedullary accumulation of leukemic cells typically is referred to as myeloid sarcoma, while leukemia cutis serves as a general term for specific skin involvement.¹⁰ In rare instances, cutaneous lesions may manifest as the initial sign of systemic disease.

Cutaneous T-cell lymphomas comprise a diverse group of non-Hodgkin lymphomas that manifest as malignant monoclonal T-lymphocyte infiltration in the skin. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T-cell lymphomas are among the key subtypes. Histologically, differentiating these conditions from benign inflammatory disorders can be challenging due to subtle features such as haloed lymphocytes, epidermotropism, and Pautrier microabscesses seen in mycosis fungoides.¹¹

Multiple myeloma involves monoclonal plasma cell proliferation, primarily affecting bone and bone marrow. Extramedullary plasmacytomas can occur outside these sites through hematogenous spread or adjacent infiltration, while metastatic plasmacytomas result from metastasis. Cutaneous plasmacytomas may arise from hematogenous dissemination or infiltration from neighboring structures.¹²

Extranodal natural killer/T-cell lymphoma, nasal type, manifests as aggressive mid-facial necrotizing lesions with extranodal involvement, notably in the nasal/paranasal area. These lesions can cause local destruction of cartilage, bone, and soft tissues and may progress through stages or arise de novo. Diagnostic challenges arise from the historical variety of terms used to describe extranodal natural killer/T-cell lymphoma, including midline lethal granuloma and lymphomatoid granulomatosis.¹³

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

Cutaneous plasmacytoma initially was suspected because of the patient’s history of monoclonal gammopathy as well as angiosarcoma due to the purpuric vascular appearance of the lesions. However, histopathology revealed a pleomorphic cellular dermal infiltrate characterized by atypical cells with mediumlarge nuclei, fine chromatin, and small nucleoli; the cells also had little cytoplasm (Figure). The infiltrate did not involve the epidermis but extended into the subcutaneous tissue. Immunohistochemistry revealed that the cells were positive for CD45, CD43, CD4, CD7, CD56, CD123, CD33, T-cell leukemia/lymphoma protein 1, and CD68. The cells were negative for CD2, CD3, CD5, CD8, T-cell intracellular antigen 1, CD13, CD15, CD19, CD20, CD21, CD23, cyclin D1, Bcl-2, Bcl-6, CD10, PAX5, MUM1, lysozyme, myeloperoxidase, perforin, granzyme B, CD57, CD34, CD117, terminal deoxynucleotidyl transferase, activin receptorlike kinase 1 βF1, Epstein-Barr virus– encoded small RNA, CD30, CD163, and pancytokeratin. Thus, the clinical and histopathologic findings led to a diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare and aggressive hematologic malignancy.

CT113003025_e_FigAB.jpg

Blastic plasmacytoid dendritic cell neoplasm affects males older than 60 years.¹ It is characterized by the clonal proliferation of precursor plasmacytoid dendritic cells—otherwise known as professional type I interferonproducing cells or plasmacytoid monocytes—of myeloid origin. Plasmacytoid dendritic cells have been renamed on several occasions, reflecting uncertainties of their histogenesis. The diagnosis of BPDCN requires a biopsy showing the morphology of plasmacytoid dendritic blast cells and immunophenotypic criteria established by either immunohistochemistry or flow cytometry.^2,3 Tumor cells morphologically show an immature blastic appearance, and the diagnosis rests upon the demonstration of CD4 and CD56, together with markers more restricted to plasmacytoid dendritic cells (eg, BDCA-2, CD123, T-cell leukemia/lymphoma protein 1, CD2AP, BCL11A) and negativity for lymphoid and myeloid lineage–associated antigens.^1,4

Blastic plasmacytoid dendritic cell neoplasms account for less than 1% of all hematopoietic neoplasms. Cutaneous lesions occur in 64% of patients with the disease and often are the reason patients seek medical care.⁵ Clinical findings include numerous erythematous and violaceous papules, nodules, and plaques that resemble purpura or vasculitis. Cutaneous lesions can vary in size from a few millimeters to 10 cm and vary in color. Moreover, patients often present with bruiselike patches, disseminated lesions, or mucosal lesions.¹ Extracutaneous involvement includes lymphadenopathy, splenomegaly, and cytopenia caused by bone marrow infiltration, which may be present at diagnosis or during disease progression. Bone marrow involvement often is present with thrombocytopenia, anemia, and neutropenia. One-third of patients with BPDCN have central nervous system involvement and no disease relapse.⁶ Other affected sites include the liver, lungs, tonsils, soft tissues, and eyes. Patients with BPDCN may present with a history of myeloid neoplasms, such as acute/chronic myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome.⁴ Our case highlights the importance of skin biopsy for making the correct diagnosis, as BPDCN manifests with cutaneous lesions that are nonspecific for neoplastic or nonneoplastic etiologies.

Given the aggressive nature of BPDCN, along with its potential for acute leukemic transformation, treatment has been challenging due to both poor response rates and lack of consensus and treatment strategies. Historically, patients who have received high-dose acute leukemia–based chemotherapy followed by an allogeneic stem cell transplant during the first remission appeared to have the best outcomes.⁷ Conventional treatments have included surgical excision with radiation and various leukemia-based chemotherapy regimens, with hyper- CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone-methotrexate, and cytarabine) being the most commonly used regimen.^7,8 Venetoclax, a B-cell lymphoma 2 protein inhibitor, has shown promise when used in combination with hyper-CVAD. For older patients who may not tolerate aggressive chemotherapy, hypomethylating agents are preferred for their tolerability. Although tagraxofusp, a CD123-directed cytotoxin, has been utilized, Sapienza et al⁹ demonstrated an association with capillary leak syndrome.

Leukemia cutis is characterized by infiltration of the skin by malignant leukocytes, often associated with a prior diagnosis of systemic leukemia or myelodysplasia. Extramedullary accumulation of leukemic cells typically is referred to as myeloid sarcoma, while leukemia cutis serves as a general term for specific skin involvement.¹⁰ In rare instances, cutaneous lesions may manifest as the initial sign of systemic disease.

Cutaneous T-cell lymphomas comprise a diverse group of non-Hodgkin lymphomas that manifest as malignant monoclonal T-lymphocyte infiltration in the skin. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T-cell lymphomas are among the key subtypes. Histologically, differentiating these conditions from benign inflammatory disorders can be challenging due to subtle features such as haloed lymphocytes, epidermotropism, and Pautrier microabscesses seen in mycosis fungoides.¹¹

Multiple myeloma involves monoclonal plasma cell proliferation, primarily affecting bone and bone marrow. Extramedullary plasmacytomas can occur outside these sites through hematogenous spread or adjacent infiltration, while metastatic plasmacytomas result from metastasis. Cutaneous plasmacytomas may arise from hematogenous dissemination or infiltration from neighboring structures.¹²

Extranodal natural killer/T-cell lymphoma, nasal type, manifests as aggressive mid-facial necrotizing lesions with extranodal involvement, notably in the nasal/paranasal area. These lesions can cause local destruction of cartilage, bone, and soft tissues and may progress through stages or arise de novo. Diagnostic challenges arise from the historical variety of terms used to describe extranodal natural killer/T-cell lymphoma, including midline lethal granuloma and lymphomatoid granulomatosis.¹³

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

CT113003010_e_ABC.jpg

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

CT113003010_e_ABC.jpg

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

CT113003010_e_ABC.jpg

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

The Diagnosis: Gastric Acid Dermatitis

After further discussion, the patient indicated that he had vomited during the night of alcohol consumption, and the vomitus remained on the affected areas until the next morning, indicating that excessive alcohol ingestion stimulated abundant secretion of gastric acid, which caused the symptoms. Additionally, the presence of clothing acted as a buffer in the unaffected areas, which helped make the final diagnosis of gastric acid dermatitis. The patient was treated with external application of recombinant bovine basic fibroblast growth factor gel (21,000 IU/5 g) once daily, and the lesions greatly improved within 7 days. The burning pain of the throat, stomach, and esophagus resolved after consultation with an otolaryngologist and a gastroenterologist.

Gastric acid dermatitis is a new term used to describe an acute skin burn caused by the patient's own gastric acid. Generally, the pH of human gastric acid is between 0.9 and 1.8 but will be diluted after eating and will gradually increase to approximately 3.5, which is not enough to induce burns on the skin.¹ In addition, the skin barrier is capable of preventing transient gastric acid corrosion.^2,3 However, the release of a large amount of gastric acid after excessive alcohol ingestion coupled with 1 night of lethargy left enough acid and time to induce skin burns in our patient.

Dermatitis caused by other allergic or chemical factors, such as Paederus dermatitis, was excluded, as the patient’s manifestation occurred during the inactive period of Paederus fuscipes. Furthermore, the patient denied any history of contact with chemicals in the last month. Food eruptions primarily manifest as systemic anaphylaxis with eruptive and pruritic rashes after consumption of seafood, eggs, milk, or other proteins, while alcoholic contact dermatitis is a form of irritating dermatitis that could be easily induced again by direct skin contact with alcohol.

Management of gastric acid dermatitis is similar to that for other chemical burns. Because scarring seldom occurs, the central issue is to restore the skin barrier as quickly as possible and to avoid or alleviate postinflammatory hyperpigmentation. Treatments to restore the skin barrier include recombinant bovine or human-derived basic fibroblast growth factor gel, moist exposed burn ointment, and medical sodium hyaluronate gelatin. To treat postinflammatory hyperpigmentation, some whitening agents such as compound superoxide dismutase arbutin cream and hydroquinone cream as well as the Q-switched Nd:YAG laser are effective to ameliorate the skin condition. If skin burns are on sun-exposed areas, photoprotection is necessary to prevent hyperpigmentation.

Acknowledgment—We thank the patient for granting permission to publish this information.

The Diagnosis: Gastric Acid Dermatitis

After further discussion, the patient indicated that he had vomited during the night of alcohol consumption, and the vomitus remained on the affected areas until the next morning, indicating that excessive alcohol ingestion stimulated abundant secretion of gastric acid, which caused the symptoms. Additionally, the presence of clothing acted as a buffer in the unaffected areas, which helped make the final diagnosis of gastric acid dermatitis. The patient was treated with external application of recombinant bovine basic fibroblast growth factor gel (21,000 IU/5 g) once daily, and the lesions greatly improved within 7 days. The burning pain of the throat, stomach, and esophagus resolved after consultation with an otolaryngologist and a gastroenterologist.

Gastric acid dermatitis is a new term used to describe an acute skin burn caused by the patient's own gastric acid. Generally, the pH of human gastric acid is between 0.9 and 1.8 but will be diluted after eating and will gradually increase to approximately 3.5, which is not enough to induce burns on the skin.¹ In addition, the skin barrier is capable of preventing transient gastric acid corrosion.^2,3 However, the release of a large amount of gastric acid after excessive alcohol ingestion coupled with 1 night of lethargy left enough acid and time to induce skin burns in our patient.

Dermatitis caused by other allergic or chemical factors, such as Paederus dermatitis, was excluded, as the patient’s manifestation occurred during the inactive period of Paederus fuscipes. Furthermore, the patient denied any history of contact with chemicals in the last month. Food eruptions primarily manifest as systemic anaphylaxis with eruptive and pruritic rashes after consumption of seafood, eggs, milk, or other proteins, while alcoholic contact dermatitis is a form of irritating dermatitis that could be easily induced again by direct skin contact with alcohol.

Management of gastric acid dermatitis is similar to that for other chemical burns. Because scarring seldom occurs, the central issue is to restore the skin barrier as quickly as possible and to avoid or alleviate postinflammatory hyperpigmentation. Treatments to restore the skin barrier include recombinant bovine or human-derived basic fibroblast growth factor gel, moist exposed burn ointment, and medical sodium hyaluronate gelatin. To treat postinflammatory hyperpigmentation, some whitening agents such as compound superoxide dismutase arbutin cream and hydroquinone cream as well as the Q-switched Nd:YAG laser are effective to ameliorate the skin condition. If skin burns are on sun-exposed areas, photoprotection is necessary to prevent hyperpigmentation.

Acknowledgment—We thank the patient for granting permission to publish this information.

The Diagnosis: Gastric Acid Dermatitis

After further discussion, the patient indicated that he had vomited during the night of alcohol consumption, and the vomitus remained on the affected areas until the next morning, indicating that excessive alcohol ingestion stimulated abundant secretion of gastric acid, which caused the symptoms. Additionally, the presence of clothing acted as a buffer in the unaffected areas, which helped make the final diagnosis of gastric acid dermatitis. The patient was treated with external application of recombinant bovine basic fibroblast growth factor gel (21,000 IU/5 g) once daily, and the lesions greatly improved within 7 days. The burning pain of the throat, stomach, and esophagus resolved after consultation with an otolaryngologist and a gastroenterologist.

Gastric acid dermatitis is a new term used to describe an acute skin burn caused by the patient's own gastric acid. Generally, the pH of human gastric acid is between 0.9 and 1.8 but will be diluted after eating and will gradually increase to approximately 3.5, which is not enough to induce burns on the skin.¹ In addition, the skin barrier is capable of preventing transient gastric acid corrosion.^2,3 However, the release of a large amount of gastric acid after excessive alcohol ingestion coupled with 1 night of lethargy left enough acid and time to induce skin burns in our patient.

Dermatitis caused by other allergic or chemical factors, such as Paederus dermatitis, was excluded, as the patient’s manifestation occurred during the inactive period of Paederus fuscipes. Furthermore, the patient denied any history of contact with chemicals in the last month. Food eruptions primarily manifest as systemic anaphylaxis with eruptive and pruritic rashes after consumption of seafood, eggs, milk, or other proteins, while alcoholic contact dermatitis is a form of irritating dermatitis that could be easily induced again by direct skin contact with alcohol.

Management of gastric acid dermatitis is similar to that for other chemical burns. Because scarring seldom occurs, the central issue is to restore the skin barrier as quickly as possible and to avoid or alleviate postinflammatory hyperpigmentation. Treatments to restore the skin barrier include recombinant bovine or human-derived basic fibroblast growth factor gel, moist exposed burn ointment, and medical sodium hyaluronate gelatin. To treat postinflammatory hyperpigmentation, some whitening agents such as compound superoxide dismutase arbutin cream and hydroquinone cream as well as the Q-switched Nd:YAG laser are effective to ameliorate the skin condition. If skin burns are on sun-exposed areas, photoprotection is necessary to prevent hyperpigmentation.

Acknowledgment—We thank the patient for granting permission to publish this information.

The Diagnosis: Granular Parakeratosis

Histopathology demonstrated diffuse parakeratosis with retention of keratohyalin granules throughout the stratum corneum consistent with a diagnosis of granular parakeratosis (Figure), a rare benign cutaneous condition that is thought to occur due to a defect in epidermal differentiation. The lesion resolved without additional treatment.

Yamamoto_Figure.jpg

The pathogenesis of granular parakeratosis is unclear, but a reactive process in which locoregional irritation or occlusion prompts increased cell turnover and prevention of profilaggrin breakdown has been proposed.^1,2 The diagnosis is linked to various precipitating agents, most commonly topical products (eg, zinc oxide, antiperspirants) and products with benzalkonium chloride (eg, laundry rinses). These agents are thought to cause retention of keratohyalin granules in the stratum corneum during epidermal differentiation.^1,2

Most affected patients are middle-aged women (mean age at diagnosis, 37.8 years).² Patients present with eruptions of erythematous, brown, hyperkeratotic patches and papules that coalesce into plaques.^1,2 These lesions can be pruritic and painful or asymptomatic. They often manifest bilaterally in intertriginous sites, most commonly the axillae, groin, or inguinal folds.^1,2

Treatment involves identification and removal of potential triggers including changing antiperspirants, limiting use of irritating agents (eg, topical products with strong fragrances), and reducing heat and moisture in the affected areas. If the lesion persists, stepwise treatment can be initiated with topical agents (eg, corticosteroids, vitamin D analogues, retinoids, keratolytics, calcineurin inhibitors) followed by systemic medications (eg, antibiotics, isotretinoin, antifungals, dexamethasone) and procedures (eg, botulinum toxin injections, surgery, laser, cryotherapy).^1,2

Unilateral granular parakeratosis, as seen in our patient, is an uncommon manifestation. Our case supports the theory that occlusion is a precipitating factor for this condition, given persistent axillary exposure to heat, sweat, and friction in the setting of limb immobilization.³

Granular parakeratosis is a challenge to diagnose due to clinical overlap with several other cutaneous conditions; histopathologic confirmation is required. Fox- Fordyce disease is a rare condition that is thought to result from keratin buildup or occlusion of apocrine or apoeccrine sweat ducts leading to duct rupture and surrounding inflammation.⁴ Common triggers include laser hair removal, hormonal changes, and living conditions that promote hot and humid environments.⁵ It can manifest similarly to granular parakeratosis, with eruptions of multiple red-violet papules that appear bilaterally in aprocine gland–rich areas, including the axillae and less commonly the genital, periareolar, thoracic, abdominal, and facial areas.^4,5 However, most patients with Fox-Fordyce disease tend to be younger females (aged 13–35 years) with severely pruritic lesions,^4,5 unlike our patient. In addition, histopathology shows hyperkeratosis, hair follicle plugging, and sweat gland and duct dilation.⁴

Seborrheic keratoses are common benign epidermal tumors caused by an overproliferation of immature keratinocytes.^6,7 Similar to granular parakeratosis, they commonly manifest in older adults as hyperpigmented, well-demarcated, verrucous plaques with a hyperkeratotic surface.⁶ However, they are more common on the face, neck, trunk, and extremities, and they tend to be asymptomatic, differentiating them from granular parakerosis.⁶ Histopathology demonstrates a papillomatous epidermal surface, large capillaries in the dermal papillae, and intraepidermal and pseudohorn epidermal cysts.⁷

Inverse lichen planus, a variant of lichen planus, is a rare inflammatory condition that involves the lysis of basal keratinocytes by CD8+ lymphocytes.⁸ Similar to granular parakeratosis, lichen planus commonly affects middle-aged women (aged 30–60 years), and this particular variant manifests with asymptomatic or mildly pruritic, hyperpigmented patches and plaques in intertriginous areas. Although it also shows hyperkeratosis on histopathology, it can be differentiated from granular parakeratosis by the additional findings of epidermal hypergranulosis, sawtooth acanthosis of rete ridges, apoptotic keratinocytes in the dermoepidermal junction, and lymphocytic infiltrate in the upper dermis.⁸

Hailey-Hailey disease (also known as familial benign pemphigus) is a rare condition caused by an autosomaldominant mutation affecting intracellular calcium signaling that impairs keratinocyte adhesion.⁹ Similar to granular parakeratosis, it is most common in middle-aged adults (aged 30–40 years) and manifests as pruritic and burning lesions in symmetric intertriginous areas that also can be triggered by heat and sweating. However, patients present with recurrent blistering and vesicular lesions that may lead to erosions and secondary infections, which reduced clinical suspicion for this diagnosis in our patient. Histopathology shows suprabasilar and intraepidermal clefts, full-thickness acantholysis, protruding dermal papillae, and a perivascular lymphocytic infiltrate in the superficial dermis.⁹

The Diagnosis: Granular Parakeratosis

Histopathology demonstrated diffuse parakeratosis with retention of keratohyalin granules throughout the stratum corneum consistent with a diagnosis of granular parakeratosis (Figure), a rare benign cutaneous condition that is thought to occur due to a defect in epidermal differentiation. The lesion resolved without additional treatment.

Yamamoto_Figure.jpg

The pathogenesis of granular parakeratosis is unclear, but a reactive process in which locoregional irritation or occlusion prompts increased cell turnover and prevention of profilaggrin breakdown has been proposed.^1,2 The diagnosis is linked to various precipitating agents, most commonly topical products (eg, zinc oxide, antiperspirants) and products with benzalkonium chloride (eg, laundry rinses). These agents are thought to cause retention of keratohyalin granules in the stratum corneum during epidermal differentiation.^1,2

Most affected patients are middle-aged women (mean age at diagnosis, 37.8 years).² Patients present with eruptions of erythematous, brown, hyperkeratotic patches and papules that coalesce into plaques.^1,2 These lesions can be pruritic and painful or asymptomatic. They often manifest bilaterally in intertriginous sites, most commonly the axillae, groin, or inguinal folds.^1,2

Treatment involves identification and removal of potential triggers including changing antiperspirants, limiting use of irritating agents (eg, topical products with strong fragrances), and reducing heat and moisture in the affected areas. If the lesion persists, stepwise treatment can be initiated with topical agents (eg, corticosteroids, vitamin D analogues, retinoids, keratolytics, calcineurin inhibitors) followed by systemic medications (eg, antibiotics, isotretinoin, antifungals, dexamethasone) and procedures (eg, botulinum toxin injections, surgery, laser, cryotherapy).^1,2

Unilateral granular parakeratosis, as seen in our patient, is an uncommon manifestation. Our case supports the theory that occlusion is a precipitating factor for this condition, given persistent axillary exposure to heat, sweat, and friction in the setting of limb immobilization.³

Granular parakeratosis is a challenge to diagnose due to clinical overlap with several other cutaneous conditions; histopathologic confirmation is required. Fox- Fordyce disease is a rare condition that is thought to result from keratin buildup or occlusion of apocrine or apoeccrine sweat ducts leading to duct rupture and surrounding inflammation.⁴ Common triggers include laser hair removal, hormonal changes, and living conditions that promote hot and humid environments.⁵ It can manifest similarly to granular parakeratosis, with eruptions of multiple red-violet papules that appear bilaterally in aprocine gland–rich areas, including the axillae and less commonly the genital, periareolar, thoracic, abdominal, and facial areas.^4,5 However, most patients with Fox-Fordyce disease tend to be younger females (aged 13–35 years) with severely pruritic lesions,^4,5 unlike our patient. In addition, histopathology shows hyperkeratosis, hair follicle plugging, and sweat gland and duct dilation.⁴

Seborrheic keratoses are common benign epidermal tumors caused by an overproliferation of immature keratinocytes.^6,7 Similar to granular parakeratosis, they commonly manifest in older adults as hyperpigmented, well-demarcated, verrucous plaques with a hyperkeratotic surface.⁶ However, they are more common on the face, neck, trunk, and extremities, and they tend to be asymptomatic, differentiating them from granular parakerosis.⁶ Histopathology demonstrates a papillomatous epidermal surface, large capillaries in the dermal papillae, and intraepidermal and pseudohorn epidermal cysts.⁷

Inverse lichen planus, a variant of lichen planus, is a rare inflammatory condition that involves the lysis of basal keratinocytes by CD8+ lymphocytes.⁸ Similar to granular parakeratosis, lichen planus commonly affects middle-aged women (aged 30–60 years), and this particular variant manifests with asymptomatic or mildly pruritic, hyperpigmented patches and plaques in intertriginous areas. Although it also shows hyperkeratosis on histopathology, it can be differentiated from granular parakeratosis by the additional findings of epidermal hypergranulosis, sawtooth acanthosis of rete ridges, apoptotic keratinocytes in the dermoepidermal junction, and lymphocytic infiltrate in the upper dermis.⁸

Hailey-Hailey disease (also known as familial benign pemphigus) is a rare condition caused by an autosomaldominant mutation affecting intracellular calcium signaling that impairs keratinocyte adhesion.⁹ Similar to granular parakeratosis, it is most common in middle-aged adults (aged 30–40 years) and manifests as pruritic and burning lesions in symmetric intertriginous areas that also can be triggered by heat and sweating. However, patients present with recurrent blistering and vesicular lesions that may lead to erosions and secondary infections, which reduced clinical suspicion for this diagnosis in our patient. Histopathology shows suprabasilar and intraepidermal clefts, full-thickness acantholysis, protruding dermal papillae, and a perivascular lymphocytic infiltrate in the superficial dermis.⁹

The Diagnosis: Granular Parakeratosis

Histopathology demonstrated diffuse parakeratosis with retention of keratohyalin granules throughout the stratum corneum consistent with a diagnosis of granular parakeratosis (Figure), a rare benign cutaneous condition that is thought to occur due to a defect in epidermal differentiation. The lesion resolved without additional treatment.

Yamamoto_Figure.jpg

The pathogenesis of granular parakeratosis is unclear, but a reactive process in which locoregional irritation or occlusion prompts increased cell turnover and prevention of profilaggrin breakdown has been proposed.^1,2 The diagnosis is linked to various precipitating agents, most commonly topical products (eg, zinc oxide, antiperspirants) and products with benzalkonium chloride (eg, laundry rinses). These agents are thought to cause retention of keratohyalin granules in the stratum corneum during epidermal differentiation.^1,2

Most affected patients are middle-aged women (mean age at diagnosis, 37.8 years).² Patients present with eruptions of erythematous, brown, hyperkeratotic patches and papules that coalesce into plaques.^1,2 These lesions can be pruritic and painful or asymptomatic. They often manifest bilaterally in intertriginous sites, most commonly the axillae, groin, or inguinal folds.^1,2

Treatment involves identification and removal of potential triggers including changing antiperspirants, limiting use of irritating agents (eg, topical products with strong fragrances), and reducing heat and moisture in the affected areas. If the lesion persists, stepwise treatment can be initiated with topical agents (eg, corticosteroids, vitamin D analogues, retinoids, keratolytics, calcineurin inhibitors) followed by systemic medications (eg, antibiotics, isotretinoin, antifungals, dexamethasone) and procedures (eg, botulinum toxin injections, surgery, laser, cryotherapy).^1,2

Unilateral granular parakeratosis, as seen in our patient, is an uncommon manifestation. Our case supports the theory that occlusion is a precipitating factor for this condition, given persistent axillary exposure to heat, sweat, and friction in the setting of limb immobilization.³

Granular parakeratosis is a challenge to diagnose due to clinical overlap with several other cutaneous conditions; histopathologic confirmation is required. Fox- Fordyce disease is a rare condition that is thought to result from keratin buildup or occlusion of apocrine or apoeccrine sweat ducts leading to duct rupture and surrounding inflammation.⁴ Common triggers include laser hair removal, hormonal changes, and living conditions that promote hot and humid environments.⁵ It can manifest similarly to granular parakeratosis, with eruptions of multiple red-violet papules that appear bilaterally in aprocine gland–rich areas, including the axillae and less commonly the genital, periareolar, thoracic, abdominal, and facial areas.^4,5 However, most patients with Fox-Fordyce disease tend to be younger females (aged 13–35 years) with severely pruritic lesions,^4,5 unlike our patient. In addition, histopathology shows hyperkeratosis, hair follicle plugging, and sweat gland and duct dilation.⁴

Seborrheic keratoses are common benign epidermal tumors caused by an overproliferation of immature keratinocytes.^6,7 Similar to granular parakeratosis, they commonly manifest in older adults as hyperpigmented, well-demarcated, verrucous plaques with a hyperkeratotic surface.⁶ However, they are more common on the face, neck, trunk, and extremities, and they tend to be asymptomatic, differentiating them from granular parakerosis.⁶ Histopathology demonstrates a papillomatous epidermal surface, large capillaries in the dermal papillae, and intraepidermal and pseudohorn epidermal cysts.⁷

Inverse lichen planus, a variant of lichen planus, is a rare inflammatory condition that involves the lysis of basal keratinocytes by CD8+ lymphocytes.⁸ Similar to granular parakeratosis, lichen planus commonly affects middle-aged women (aged 30–60 years), and this particular variant manifests with asymptomatic or mildly pruritic, hyperpigmented patches and plaques in intertriginous areas. Although it also shows hyperkeratosis on histopathology, it can be differentiated from granular parakeratosis by the additional findings of epidermal hypergranulosis, sawtooth acanthosis of rete ridges, apoptotic keratinocytes in the dermoepidermal junction, and lymphocytic infiltrate in the upper dermis.⁸

Hailey-Hailey disease (also known as familial benign pemphigus) is a rare condition caused by an autosomaldominant mutation affecting intracellular calcium signaling that impairs keratinocyte adhesion.⁹ Similar to granular parakeratosis, it is most common in middle-aged adults (aged 30–40 years) and manifests as pruritic and burning lesions in symmetric intertriginous areas that also can be triggered by heat and sweating. However, patients present with recurrent blistering and vesicular lesions that may lead to erosions and secondary infections, which reduced clinical suspicion for this diagnosis in our patient. Histopathology shows suprabasilar and intraepidermal clefts, full-thickness acantholysis, protruding dermal papillae, and a perivascular lymphocytic infiltrate in the superficial dermis.⁹

The Diagnosis: Pellagra

The patient was diagnosed with pellagra based on the clinical and laboratory findings. He was discharged with nicotinamide 250 mg and folic acid 5 mg supplementation daily. After 3 months, all symptoms resolved.

Pellagra is a condition usually associated with the 4 Ds: dermatitis; diarrhea; dementia; and, if untreated, death.¹ The word pellagra is derived from the Italian terms pelle and agra, which mean skin and rough, respectively.² Spanish physician Gasper Casal first described pellagra in 1762 after observing the disease in poorer peasants in Asturias who mainly relied on maize and rarely consumed fresh meat.^1,2 Joseph Goldberger conducted research in the early 20th century, provoking the disease in jail prisoners by modifying their diets. However, it was not until 1926 that Goldberger discovered the true cause of the illness to be a poor diet and named what would become known as nicotinamide as the pellagra preventative factor.^1,2 Niacin (vitamin B3), the deficient molecule in pellagra, also is known as nicotinic acid, nicotinamide, or niacinamide. It is a water-soluble vitamin that is converted into nicotinamide-adenine-dinucleotide (NAD) and its phosphate NADP.^1,2 It has been hypothesized that pellagra symptoms arise from insufficient amounts of NAD and NADP, making the body unable to support cellular energy transfer processes.³

Pellagra manifests 50 to 60 days after starting a diet low in niacin. Niacin and nicotinamide are absorbed from the digested food to the stomach through a sodiumdependent mechanism, and then nicotinamide may be transformed into nicotinic acid with microsomal deamidation.³ Niacin may be obtained from one’s diet or produced from tryptophan. Foods with the highest amounts of niacin include liver, poultry, fish, eggs, milk, pork, mushrooms, avocados, almonds, and legumes.^1,3 Coffee also contains trigonelline, which may be transformed into nicotinic acid when roasted, increasing the niacin level by 30 times.³ Approximately 60 mg of dietary tryptophan is needed to produce up to 1 mg of niacin in the presence of B2 and B6 vitamins. This mechanism provides approximately half of the needs for niacin.3 Insufficient dietary intake of niacin or the essential amino acid tryptophan can cause pellagra (primary pellagra), which is a concern in resource-limited countries. Alternatively, the body may not be able to properly utilize niacin for metabolic processes (secondary pellagra), which occurs more frequently in developed countries.¹ Secondary pellagra also may be caused by alcoholism, colitis, cirrhosis, carcinoid tumors, Hartnup disease, or gastrointestinal tuberculosis, as these conditions prevent niacin from being consumed, absorbed, or processed. Certain medications can cause pellagra by interfering with the tryptophan-niacin pathway, including isoniazid, 5-fluorouracil, pyrazinamide, 6-mercaptopurine, hydantoins, ethionamide, phenobarbital, azathioprine, and chloramphenicol.²

The clinical manifestations of pellagra are diverse because it affects tissues with high turnover rates. Clinical features of pellagra include symmetric photosensitive skin eruptions, gastrointestinal tract symptoms, and neurologic and mental disorders.³ The first signs of pellagra may include muscle weakness, digestive concerns, and psychological or emotional discomfort.² Pellagra dermatitis manifests as an acute or intermittent, bilaterally symmetrical eruption on sun-exposed areas and is markedly distinct from healthy skin.³ Some individuals may experience vesiculation and bullae development (wet pellagra). The erythema is first brilliant red then turns into a cinnamon-brown color. Over time, the skin becomes thickened, scaly, cracked, and hyperpigmented.¹ The dryness of the skin likely is due to a remarkable decrease in wax ester and sebaceous gland atrophy seen on histopathology.⁴ Pellagra most frequently affects the back of the hands (77%–97% of cases), which can extend upward to create the so-called pellagra glove or gauntlet.³ It is common to see symmetrical eruptions in the shape of a butterfly following an anatomical pattern innervated by the trigeminal nerve, which resembles lupus erythematosus on the face. Another common manifestation is Casal necklace, a well-marginated eruption frequently seen on the front of the neck (Figure).² On the foot, lesions often do not develop close to the malleoli but rather terminate distally on the backs of the toes. Sometimes a boot pattern may form that covers the front and back of the leg.^1-3

Mioso_Figure.jpg

The pathophysiology of photosensitivity in pellagra was hypothesized by Karthikeyan and Thappa.³ They discovered an excessive synthesis of a phototoxic substance, kynurenic acid, and a deficiency in urocanic acid, which normally protects the skin by absorbing light in the UVB range. Niacin deprivation leads to the production of kynurenic acid through the tryptophan-kynurenine-nicotinic acid pathway and reduces the amount of urocanic acid by affecting the enzyme histidase in the stratum corneum.^1-3 In one-third of patients, pellagra affects the oral mucosa, causing characteristic symptoms such as glossitis, angular stomatitis, and cheilitis.² In nearly 50% of patients, poor appetite, nausea, epigastric discomfort, diarrhea, and excessive salivation are present. Most of the gastrointestinal tract is affected by mucosal inflammation and atrophy, which can cause malnutrition and cachexia due to anorexia and malabsorptive diarrhea.² Headache, irritability, poor concentration, hallucinations, photophobia, tremor, and depression are some of the neuropsychiatric symptoms. Patients experience delirium and disorientation as pellagra progresses, followed by a comatose state and ultimately death.²

The patient’s history and physical examination are used to make the diagnosis, with particular attention to the patient’s dietary details. The diagnosis is made in part ex juvantibus by seeing how the patient responds to higher niacin doses. Anemia, hypoproteinemia, elevated blood calcium, reduced serum potassium and phosphorus, abnormal liver function tests, and elevated serum porphyrin levels also indicate pellagra. Niacin 300 mg in divided doses for up to 4 weeks has been recommended by the World Health Organization to treat pellagra.⁵ The flushing seen with niacin administration is not linked to the usage of nicotinamide. The recommended nicotinamide dosage for adults is 100 mg orally every 6 hours until most acute symptoms have disappeared, followed by oral administration of 50 mg every 8 to 12 hours until all skin lesions have healed.²

Among the differential diagnoses, necrolytic migratory erythema is characterized by an episodic eruption of crusted, erosive, annular erythematous plaques with blister development, which occurs in 70% of patients with glucagonoma syndrome. The perioral region, perineum, lower belly, thighs, and distal extremities are the usual locations.^6,7 Laboratory test results include elevated fasting serum glucagon (>1000 ng/L) and normocytic anemia, which aided in ruling out this diagnosis in our patient. Generalized acute cutaneous lupus erythematosus may appear as a broad morbilliform eruption. The hands frequently exhibit erythema and edema, especially across the dorsal and interphalangeal regions.8 Other typical findings of systemic lupus erythematosus such as antinuclear antibody were not seen in our patient, making this diagnosis unlikely. Porphyria cutanea tarda also must be considered in the differential diagnosis. The hepatic deficiency of uroporphyrinogen decarboxylase is the primary cause of this condition. Although it is characterized by blistering lesions, patients more frequently describe increased skin fragility in sun-exposed regions. Hypertrichosis, hyperpigmentation or hypopigmentation, hirsutism, or scarring may appear in the later stage of the disease.9 Phototoxic reaction was ruled out because the patient spent most of the time at home, and no new drugs had been prescribed in the previous months.

The Diagnosis: Pellagra

The patient was diagnosed with pellagra based on the clinical and laboratory findings. He was discharged with nicotinamide 250 mg and folic acid 5 mg supplementation daily. After 3 months, all symptoms resolved.

Pellagra is a condition usually associated with the 4 Ds: dermatitis; diarrhea; dementia; and, if untreated, death.¹ The word pellagra is derived from the Italian terms pelle and agra, which mean skin and rough, respectively.² Spanish physician Gasper Casal first described pellagra in 1762 after observing the disease in poorer peasants in Asturias who mainly relied on maize and rarely consumed fresh meat.^1,2 Joseph Goldberger conducted research in the early 20th century, provoking the disease in jail prisoners by modifying their diets. However, it was not until 1926 that Goldberger discovered the true cause of the illness to be a poor diet and named what would become known as nicotinamide as the pellagra preventative factor.^1,2 Niacin (vitamin B3), the deficient molecule in pellagra, also is known as nicotinic acid, nicotinamide, or niacinamide. It is a water-soluble vitamin that is converted into nicotinamide-adenine-dinucleotide (NAD) and its phosphate NADP.^1,2 It has been hypothesized that pellagra symptoms arise from insufficient amounts of NAD and NADP, making the body unable to support cellular energy transfer processes.³

Pellagra manifests 50 to 60 days after starting a diet low in niacin. Niacin and nicotinamide are absorbed from the digested food to the stomach through a sodiumdependent mechanism, and then nicotinamide may be transformed into nicotinic acid with microsomal deamidation.³ Niacin may be obtained from one’s diet or produced from tryptophan. Foods with the highest amounts of niacin include liver, poultry, fish, eggs, milk, pork, mushrooms, avocados, almonds, and legumes.^1,3 Coffee also contains trigonelline, which may be transformed into nicotinic acid when roasted, increasing the niacin level by 30 times.³ Approximately 60 mg of dietary tryptophan is needed to produce up to 1 mg of niacin in the presence of B2 and B6 vitamins. This mechanism provides approximately half of the needs for niacin.3 Insufficient dietary intake of niacin or the essential amino acid tryptophan can cause pellagra (primary pellagra), which is a concern in resource-limited countries. Alternatively, the body may not be able to properly utilize niacin for metabolic processes (secondary pellagra), which occurs more frequently in developed countries.¹ Secondary pellagra also may be caused by alcoholism, colitis, cirrhosis, carcinoid tumors, Hartnup disease, or gastrointestinal tuberculosis, as these conditions prevent niacin from being consumed, absorbed, or processed. Certain medications can cause pellagra by interfering with the tryptophan-niacin pathway, including isoniazid, 5-fluorouracil, pyrazinamide, 6-mercaptopurine, hydantoins, ethionamide, phenobarbital, azathioprine, and chloramphenicol.²

The clinical manifestations of pellagra are diverse because it affects tissues with high turnover rates. Clinical features of pellagra include symmetric photosensitive skin eruptions, gastrointestinal tract symptoms, and neurologic and mental disorders.³ The first signs of pellagra may include muscle weakness, digestive concerns, and psychological or emotional discomfort.² Pellagra dermatitis manifests as an acute or intermittent, bilaterally symmetrical eruption on sun-exposed areas and is markedly distinct from healthy skin.³ Some individuals may experience vesiculation and bullae development (wet pellagra). The erythema is first brilliant red then turns into a cinnamon-brown color. Over time, the skin becomes thickened, scaly, cracked, and hyperpigmented.¹ The dryness of the skin likely is due to a remarkable decrease in wax ester and sebaceous gland atrophy seen on histopathology.⁴ Pellagra most frequently affects the back of the hands (77%–97% of cases), which can extend upward to create the so-called pellagra glove or gauntlet.³ It is common to see symmetrical eruptions in the shape of a butterfly following an anatomical pattern innervated by the trigeminal nerve, which resembles lupus erythematosus on the face. Another common manifestation is Casal necklace, a well-marginated eruption frequently seen on the front of the neck (Figure).² On the foot, lesions often do not develop close to the malleoli but rather terminate distally on the backs of the toes. Sometimes a boot pattern may form that covers the front and back of the leg.^1-3

Mioso_Figure.jpg

The pathophysiology of photosensitivity in pellagra was hypothesized by Karthikeyan and Thappa.³ They discovered an excessive synthesis of a phototoxic substance, kynurenic acid, and a deficiency in urocanic acid, which normally protects the skin by absorbing light in the UVB range. Niacin deprivation leads to the production of kynurenic acid through the tryptophan-kynurenine-nicotinic acid pathway and reduces the amount of urocanic acid by affecting the enzyme histidase in the stratum corneum.^1-3 In one-third of patients, pellagra affects the oral mucosa, causing characteristic symptoms such as glossitis, angular stomatitis, and cheilitis.² In nearly 50% of patients, poor appetite, nausea, epigastric discomfort, diarrhea, and excessive salivation are present. Most of the gastrointestinal tract is affected by mucosal inflammation and atrophy, which can cause malnutrition and cachexia due to anorexia and malabsorptive diarrhea.² Headache, irritability, poor concentration, hallucinations, photophobia, tremor, and depression are some of the neuropsychiatric symptoms. Patients experience delirium and disorientation as pellagra progresses, followed by a comatose state and ultimately death.²

The patient’s history and physical examination are used to make the diagnosis, with particular attention to the patient’s dietary details. The diagnosis is made in part ex juvantibus by seeing how the patient responds to higher niacin doses. Anemia, hypoproteinemia, elevated blood calcium, reduced serum potassium and phosphorus, abnormal liver function tests, and elevated serum porphyrin levels also indicate pellagra. Niacin 300 mg in divided doses for up to 4 weeks has been recommended by the World Health Organization to treat pellagra.⁵ The flushing seen with niacin administration is not linked to the usage of nicotinamide. The recommended nicotinamide dosage for adults is 100 mg orally every 6 hours until most acute symptoms have disappeared, followed by oral administration of 50 mg every 8 to 12 hours until all skin lesions have healed.²

Among the differential diagnoses, necrolytic migratory erythema is characterized by an episodic eruption of crusted, erosive, annular erythematous plaques with blister development, which occurs in 70% of patients with glucagonoma syndrome. The perioral region, perineum, lower belly, thighs, and distal extremities are the usual locations.^6,7 Laboratory test results include elevated fasting serum glucagon (>1000 ng/L) and normocytic anemia, which aided in ruling out this diagnosis in our patient. Generalized acute cutaneous lupus erythematosus may appear as a broad morbilliform eruption. The hands frequently exhibit erythema and edema, especially across the dorsal and interphalangeal regions.8 Other typical findings of systemic lupus erythematosus such as antinuclear antibody were not seen in our patient, making this diagnosis unlikely. Porphyria cutanea tarda also must be considered in the differential diagnosis. The hepatic deficiency of uroporphyrinogen decarboxylase is the primary cause of this condition. Although it is characterized by blistering lesions, patients more frequently describe increased skin fragility in sun-exposed regions. Hypertrichosis, hyperpigmentation or hypopigmentation, hirsutism, or scarring may appear in the later stage of the disease.9 Phototoxic reaction was ruled out because the patient spent most of the time at home, and no new drugs had been prescribed in the previous months.

The Diagnosis: Pellagra

The patient was diagnosed with pellagra based on the clinical and laboratory findings. He was discharged with nicotinamide 250 mg and folic acid 5 mg supplementation daily. After 3 months, all symptoms resolved.

Pellagra is a condition usually associated with the 4 Ds: dermatitis; diarrhea; dementia; and, if untreated, death.¹ The word pellagra is derived from the Italian terms pelle and agra, which mean skin and rough, respectively.² Spanish physician Gasper Casal first described pellagra in 1762 after observing the disease in poorer peasants in Asturias who mainly relied on maize and rarely consumed fresh meat.^1,2 Joseph Goldberger conducted research in the early 20th century, provoking the disease in jail prisoners by modifying their diets. However, it was not until 1926 that Goldberger discovered the true cause of the illness to be a poor diet and named what would become known as nicotinamide as the pellagra preventative factor.^1,2 Niacin (vitamin B3), the deficient molecule in pellagra, also is known as nicotinic acid, nicotinamide, or niacinamide. It is a water-soluble vitamin that is converted into nicotinamide-adenine-dinucleotide (NAD) and its phosphate NADP.^1,2 It has been hypothesized that pellagra symptoms arise from insufficient amounts of NAD and NADP, making the body unable to support cellular energy transfer processes.³

Pellagra manifests 50 to 60 days after starting a diet low in niacin. Niacin and nicotinamide are absorbed from the digested food to the stomach through a sodiumdependent mechanism, and then nicotinamide may be transformed into nicotinic acid with microsomal deamidation.³ Niacin may be obtained from one’s diet or produced from tryptophan. Foods with the highest amounts of niacin include liver, poultry, fish, eggs, milk, pork, mushrooms, avocados, almonds, and legumes.^1,3 Coffee also contains trigonelline, which may be transformed into nicotinic acid when roasted, increasing the niacin level by 30 times.³ Approximately 60 mg of dietary tryptophan is needed to produce up to 1 mg of niacin in the presence of B2 and B6 vitamins. This mechanism provides approximately half of the needs for niacin.3 Insufficient dietary intake of niacin or the essential amino acid tryptophan can cause pellagra (primary pellagra), which is a concern in resource-limited countries. Alternatively, the body may not be able to properly utilize niacin for metabolic processes (secondary pellagra), which occurs more frequently in developed countries.¹ Secondary pellagra also may be caused by alcoholism, colitis, cirrhosis, carcinoid tumors, Hartnup disease, or gastrointestinal tuberculosis, as these conditions prevent niacin from being consumed, absorbed, or processed. Certain medications can cause pellagra by interfering with the tryptophan-niacin pathway, including isoniazid, 5-fluorouracil, pyrazinamide, 6-mercaptopurine, hydantoins, ethionamide, phenobarbital, azathioprine, and chloramphenicol.²

The clinical manifestations of pellagra are diverse because it affects tissues with high turnover rates. Clinical features of pellagra include symmetric photosensitive skin eruptions, gastrointestinal tract symptoms, and neurologic and mental disorders.³ The first signs of pellagra may include muscle weakness, digestive concerns, and psychological or emotional discomfort.² Pellagra dermatitis manifests as an acute or intermittent, bilaterally symmetrical eruption on sun-exposed areas and is markedly distinct from healthy skin.³ Some individuals may experience vesiculation and bullae development (wet pellagra). The erythema is first brilliant red then turns into a cinnamon-brown color. Over time, the skin becomes thickened, scaly, cracked, and hyperpigmented.¹ The dryness of the skin likely is due to a remarkable decrease in wax ester and sebaceous gland atrophy seen on histopathology.⁴ Pellagra most frequently affects the back of the hands (77%–97% of cases), which can extend upward to create the so-called pellagra glove or gauntlet.³ It is common to see symmetrical eruptions in the shape of a butterfly following an anatomical pattern innervated by the trigeminal nerve, which resembles lupus erythematosus on the face. Another common manifestation is Casal necklace, a well-marginated eruption frequently seen on the front of the neck (Figure).² On the foot, lesions often do not develop close to the malleoli but rather terminate distally on the backs of the toes. Sometimes a boot pattern may form that covers the front and back of the leg.^1-3

Mioso_Figure.jpg

The pathophysiology of photosensitivity in pellagra was hypothesized by Karthikeyan and Thappa.³ They discovered an excessive synthesis of a phototoxic substance, kynurenic acid, and a deficiency in urocanic acid, which normally protects the skin by absorbing light in the UVB range. Niacin deprivation leads to the production of kynurenic acid through the tryptophan-kynurenine-nicotinic acid pathway and reduces the amount of urocanic acid by affecting the enzyme histidase in the stratum corneum.^1-3 In one-third of patients, pellagra affects the oral mucosa, causing characteristic symptoms such as glossitis, angular stomatitis, and cheilitis.² In nearly 50% of patients, poor appetite, nausea, epigastric discomfort, diarrhea, and excessive salivation are present. Most of the gastrointestinal tract is affected by mucosal inflammation and atrophy, which can cause malnutrition and cachexia due to anorexia and malabsorptive diarrhea.² Headache, irritability, poor concentration, hallucinations, photophobia, tremor, and depression are some of the neuropsychiatric symptoms. Patients experience delirium and disorientation as pellagra progresses, followed by a comatose state and ultimately death.²

The patient’s history and physical examination are used to make the diagnosis, with particular attention to the patient’s dietary details. The diagnosis is made in part ex juvantibus by seeing how the patient responds to higher niacin doses. Anemia, hypoproteinemia, elevated blood calcium, reduced serum potassium and phosphorus, abnormal liver function tests, and elevated serum porphyrin levels also indicate pellagra. Niacin 300 mg in divided doses for up to 4 weeks has been recommended by the World Health Organization to treat pellagra.⁵ The flushing seen with niacin administration is not linked to the usage of nicotinamide. The recommended nicotinamide dosage for adults is 100 mg orally every 6 hours until most acute symptoms have disappeared, followed by oral administration of 50 mg every 8 to 12 hours until all skin lesions have healed.²

Among the differential diagnoses, necrolytic migratory erythema is characterized by an episodic eruption of crusted, erosive, annular erythematous plaques with blister development, which occurs in 70% of patients with glucagonoma syndrome. The perioral region, perineum, lower belly, thighs, and distal extremities are the usual locations.^6,7 Laboratory test results include elevated fasting serum glucagon (>1000 ng/L) and normocytic anemia, which aided in ruling out this diagnosis in our patient. Generalized acute cutaneous lupus erythematosus may appear as a broad morbilliform eruption. The hands frequently exhibit erythema and edema, especially across the dorsal and interphalangeal regions.8 Other typical findings of systemic lupus erythematosus such as antinuclear antibody were not seen in our patient, making this diagnosis unlikely. Porphyria cutanea tarda also must be considered in the differential diagnosis. The hepatic deficiency of uroporphyrinogen decarboxylase is the primary cause of this condition. Although it is characterized by blistering lesions, patients more frequently describe increased skin fragility in sun-exposed regions. Hypertrichosis, hyperpigmentation or hypopigmentation, hirsutism, or scarring may appear in the later stage of the disease.9 Phototoxic reaction was ruled out because the patient spent most of the time at home, and no new drugs had been prescribed in the previous months.