Photo Challenge

The Diagnosis: Coma Blisters

Histologic examination revealed pauci-inflammatory subepidermal blisters with swelling of eccrine cells, signaling impending gland necrosis (Figure). Direct immunofluorescence testing on perilesional skin was negative. These findings would be inconsistent for diagnoses of edema blisters (most commonly seen in patients with an acute exacerbation of chronic lower extremity edema), friction blisters (intraepidermal blisters seen on histopathology), and bullous pemphigoid (linear IgG and/or C3 staining along the basement membrane zone on direct immunofluorescence testing is characteristic). Although eccrine gland alterations have been seen in toxic epidermal necrolysis,¹ the mucous membranes are involved in more than 90% of cases, making the diagnosis less likely. Furthermore, interface changes including prominent keratinocyte necrosis were not seen on histology.

Given the localized nature of the lesions in our patient and negative direct immunofluorescence studies, a diagnosis of coma blisters was made. Gentle wound care practices to the areas of denuded skin were implemented with complete resolution. The patient’s condition gradually improved, and she was extubated and discharged home.

Coma blisters are self-limited bullous lesions that have been reported in comatose patients as early as 1812 when Napoleon’s surgeon first noticed cutaneous blisters in comatose French soldiers being treated for carbon monoxide intoxication.² Since then, barbiturate overdose has remained the most common association, but coma blisters have occurred in the absence of specific drug exposures. Clinically, erythematous or violaceous plaques typically appear within 24 hours of drug ingestion, and progression to large tense bullae usually occurs within 48 to 72 hours of unconsciousness.³ They characteristically occur in pressure-dependent areas, but reports have shown lesions in non–pressure-dependent areas, including the penis and mouth.^1,4 Spontaneous resolution within 1 to 2 weeks is typical.⁵

The underlying pathogenesis remains controversial, as multiple mechanisms have been suggested, but clear causal evidence is lacking. The original proposition that direct effects of drug toxicity caused the cutaneous observations was later refuted after similar bullous lesions with eccrine gland necrosis were reported in comatose patients with neurologic conditions.⁶ It is largely accepted that pressure-induced local ischemia—proportional to the duration and amount of pressure—leads to tissue injury and is critical to the pathogenesis. During periods of ischemia, the most metabolically active tissues will undergo necrosis first; however, in eccrine glands, the earliest and most severe damage does not seem to occur in the most metabolically active cells.⁷ Additionally, this would not provide a viable explanation for coma blisters with eccrine gland necrosis developing in variable non–pressuredependent areas.

Moreover, drug- and non–drug-induced coma blisters can appear identically, but specific histopathologic differences have been reported. The most notable markers of non–drug-induced coma blisters are the absence of an inflammatory infiltrate in the epidermis and the presence of thrombosis in dermal vessels.⁸ Demonstration of necrotic changes in the secretory portion of the eccrine gland is considered the histopathologic hallmark for drug-induced coma blisters, but other findings can include subepidermal or intraepidermal bullae; perivascular infiltrates; and focal necrosis of the epidermis, dermis, subcutis, or epidermal appendages.⁶ Arteriolar wall necrosis and dermal inflammatory infiltrates also have been observed.⁷

Benzodiazepines have been widely prescribed and abused since their development, and overdose is much more common today than with barbiturates.⁹ Coma blisters rarely have been documented in the setting of isolated benzodiazepine overdose, and of the few cases, only one report implicated lorazepam as the causative agent.^4,7 The characteristic finding of eccrine gland necrosis consistently was seen in our patient. This case not only emphasizes the need for greater awareness of the association between benzodiazepine overdose and coma blisters but also the importance of clinical context when considering diagnoses. It is essential to note that coma blisters themselves are nonspecific, and the diagnosis of drug-induced coma blisters warrants confirmatory toxicologic analysis.

The Diagnosis: Coma Blisters

Histologic examination revealed pauci-inflammatory subepidermal blisters with swelling of eccrine cells, signaling impending gland necrosis (Figure). Direct immunofluorescence testing on perilesional skin was negative. These findings would be inconsistent for diagnoses of edema blisters (most commonly seen in patients with an acute exacerbation of chronic lower extremity edema), friction blisters (intraepidermal blisters seen on histopathology), and bullous pemphigoid (linear IgG and/or C3 staining along the basement membrane zone on direct immunofluorescence testing is characteristic). Although eccrine gland alterations have been seen in toxic epidermal necrolysis,¹ the mucous membranes are involved in more than 90% of cases, making the diagnosis less likely. Furthermore, interface changes including prominent keratinocyte necrosis were not seen on histology.

Given the localized nature of the lesions in our patient and negative direct immunofluorescence studies, a diagnosis of coma blisters was made. Gentle wound care practices to the areas of denuded skin were implemented with complete resolution. The patient’s condition gradually improved, and she was extubated and discharged home.

Coma blisters are self-limited bullous lesions that have been reported in comatose patients as early as 1812 when Napoleon’s surgeon first noticed cutaneous blisters in comatose French soldiers being treated for carbon monoxide intoxication.² Since then, barbiturate overdose has remained the most common association, but coma blisters have occurred in the absence of specific drug exposures. Clinically, erythematous or violaceous plaques typically appear within 24 hours of drug ingestion, and progression to large tense bullae usually occurs within 48 to 72 hours of unconsciousness.³ They characteristically occur in pressure-dependent areas, but reports have shown lesions in non–pressure-dependent areas, including the penis and mouth.^1,4 Spontaneous resolution within 1 to 2 weeks is typical.⁵

The underlying pathogenesis remains controversial, as multiple mechanisms have been suggested, but clear causal evidence is lacking. The original proposition that direct effects of drug toxicity caused the cutaneous observations was later refuted after similar bullous lesions with eccrine gland necrosis were reported in comatose patients with neurologic conditions.⁶ It is largely accepted that pressure-induced local ischemia—proportional to the duration and amount of pressure—leads to tissue injury and is critical to the pathogenesis. During periods of ischemia, the most metabolically active tissues will undergo necrosis first; however, in eccrine glands, the earliest and most severe damage does not seem to occur in the most metabolically active cells.⁷ Additionally, this would not provide a viable explanation for coma blisters with eccrine gland necrosis developing in variable non–pressuredependent areas.

Moreover, drug- and non–drug-induced coma blisters can appear identically, but specific histopathologic differences have been reported. The most notable markers of non–drug-induced coma blisters are the absence of an inflammatory infiltrate in the epidermis and the presence of thrombosis in dermal vessels.⁸ Demonstration of necrotic changes in the secretory portion of the eccrine gland is considered the histopathologic hallmark for drug-induced coma blisters, but other findings can include subepidermal or intraepidermal bullae; perivascular infiltrates; and focal necrosis of the epidermis, dermis, subcutis, or epidermal appendages.⁶ Arteriolar wall necrosis and dermal inflammatory infiltrates also have been observed.⁷

Benzodiazepines have been widely prescribed and abused since their development, and overdose is much more common today than with barbiturates.⁹ Coma blisters rarely have been documented in the setting of isolated benzodiazepine overdose, and of the few cases, only one report implicated lorazepam as the causative agent.^4,7 The characteristic finding of eccrine gland necrosis consistently was seen in our patient. This case not only emphasizes the need for greater awareness of the association between benzodiazepine overdose and coma blisters but also the importance of clinical context when considering diagnoses. It is essential to note that coma blisters themselves are nonspecific, and the diagnosis of drug-induced coma blisters warrants confirmatory toxicologic analysis.

The Diagnosis: Coma Blisters

Histologic examination revealed pauci-inflammatory subepidermal blisters with swelling of eccrine cells, signaling impending gland necrosis (Figure). Direct immunofluorescence testing on perilesional skin was negative. These findings would be inconsistent for diagnoses of edema blisters (most commonly seen in patients with an acute exacerbation of chronic lower extremity edema), friction blisters (intraepidermal blisters seen on histopathology), and bullous pemphigoid (linear IgG and/or C3 staining along the basement membrane zone on direct immunofluorescence testing is characteristic). Although eccrine gland alterations have been seen in toxic epidermal necrolysis,¹ the mucous membranes are involved in more than 90% of cases, making the diagnosis less likely. Furthermore, interface changes including prominent keratinocyte necrosis were not seen on histology.

Given the localized nature of the lesions in our patient and negative direct immunofluorescence studies, a diagnosis of coma blisters was made. Gentle wound care practices to the areas of denuded skin were implemented with complete resolution. The patient’s condition gradually improved, and she was extubated and discharged home.

Coma blisters are self-limited bullous lesions that have been reported in comatose patients as early as 1812 when Napoleon’s surgeon first noticed cutaneous blisters in comatose French soldiers being treated for carbon monoxide intoxication.² Since then, barbiturate overdose has remained the most common association, but coma blisters have occurred in the absence of specific drug exposures. Clinically, erythematous or violaceous plaques typically appear within 24 hours of drug ingestion, and progression to large tense bullae usually occurs within 48 to 72 hours of unconsciousness.³ They characteristically occur in pressure-dependent areas, but reports have shown lesions in non–pressure-dependent areas, including the penis and mouth.^1,4 Spontaneous resolution within 1 to 2 weeks is typical.⁵

The underlying pathogenesis remains controversial, as multiple mechanisms have been suggested, but clear causal evidence is lacking. The original proposition that direct effects of drug toxicity caused the cutaneous observations was later refuted after similar bullous lesions with eccrine gland necrosis were reported in comatose patients with neurologic conditions.⁶ It is largely accepted that pressure-induced local ischemia—proportional to the duration and amount of pressure—leads to tissue injury and is critical to the pathogenesis. During periods of ischemia, the most metabolically active tissues will undergo necrosis first; however, in eccrine glands, the earliest and most severe damage does not seem to occur in the most metabolically active cells.⁷ Additionally, this would not provide a viable explanation for coma blisters with eccrine gland necrosis developing in variable non–pressuredependent areas.

Moreover, drug- and non–drug-induced coma blisters can appear identically, but specific histopathologic differences have been reported. The most notable markers of non–drug-induced coma blisters are the absence of an inflammatory infiltrate in the epidermis and the presence of thrombosis in dermal vessels.⁸ Demonstration of necrotic changes in the secretory portion of the eccrine gland is considered the histopathologic hallmark for drug-induced coma blisters, but other findings can include subepidermal or intraepidermal bullae; perivascular infiltrates; and focal necrosis of the epidermis, dermis, subcutis, or epidermal appendages.⁶ Arteriolar wall necrosis and dermal inflammatory infiltrates also have been observed.⁷

Benzodiazepines have been widely prescribed and abused since their development, and overdose is much more common today than with barbiturates.⁹ Coma blisters rarely have been documented in the setting of isolated benzodiazepine overdose, and of the few cases, only one report implicated lorazepam as the causative agent.^4,7 The characteristic finding of eccrine gland necrosis consistently was seen in our patient. This case not only emphasizes the need for greater awareness of the association between benzodiazepine overdose and coma blisters but also the importance of clinical context when considering diagnoses. It is essential to note that coma blisters themselves are nonspecific, and the diagnosis of drug-induced coma blisters warrants confirmatory toxicologic analysis.

The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

THE DIAGNOSIS:

Acquired Perforating Disorder of Renal Disease

A papule with the central plug removed left a pitlike depression, representing Kyrle disease (Figure 1). A punch biopsy of the left forearm revealed epidermal hyperplasia (Figure 2A) surrounding a keratin plug that contained degenerated basophilic material (Figure 2B), confirming the diagnosis of acquired perforating disorder of renal disease (APDRD), classically described as Kyrle disease.

Acquired perforating disorder of renal disease is an uncommon condition in the general population. It is associated with systemic disease, commonly diabetes mellitus and chronic renal failure, and is seen in up to 10% patients receiving hemodialysis.¹ The underlying etiology and pathogenesis of APDRD remains unknown. It has been proposed to be a variant of prurigo nodularis, representing end-stage excoriated folliculitis.¹ Given that most cases appear in patients with systemic disease and metabolic abnormalities, APDRD also has been classified under the spectrum of acquired perforating dermatoses, a group of disorders defined by transepithelial elimination of dermal connective tissue. Elevated levels of serum and tissue fibronectin, uremia, and hyperphosphatemia have been observed in patients with APDRD.^1,2 Fibronectin stimulates epithelial migration and proliferation and may lead to expulsion of keratin. Furthermore, dermal deposition of excess urea and/or phosphate could initiate transepithelial elimination of material. Alternative hypotheses implicate abnormal keratinization or an imbalance between the rates of epidermal proliferation/ differentiation and keratin production, whereby keratin production outpaces the former. Keratin deposited within the dermis subsequently elicits an inflammatory response along with alterations in the local dermis and connective tissue. These components become intermixed and are extruded through the plug opening.³ Lastly, immune dysregulation resulting from systemic disease could contribute to APDRD through increased expression of IL-31, a cytokine thought to play a role in several pruritic inflammatory skin diseases.⁴

Although standardized treatment guidelines for APDRD have not been established, the mainstay of therapy is control of the underlying systemic disorder. Intense pruritus and repeated scratching may contribute to microtrauma and subsequent koebnerization of new lesions.³ Thus, ameliorating pruritus can provide both symptomatic relief and prevent the development of new lesions. Retinoids, UV light, oral antibiotics, antihistamines, corticosteroids, keratolytic agents, and immunosuppressants (eg, allopurinol, tacrolimus) have shown some benefit.⁴

The differential diagnoses for APDRD include arthropod hypersensitivity reactions, eruptive keratoacanthomas, keratosis pilaris, and prurigo nodularis. Arthropod hypersensitivity reactions are seen in patients with a history of a bite or sting from arthropods such as bees, fleas, mites, ticks, and spiders. These reactions cause symptoms of pain, burning, or pruritus and present heterogeneously. They can be edematous and appear as single or multiple papules, pustules, plaques, vesicles, and/or bullae. A central punctum or crusting also may be present. Eruptive keratoacanthomas are seen in Grzybowski syndrome and Ferguson-Smith disease. Grzybowski syndrome arises in the fifth to seventh decades of life and is characterized by the eruptive onset of hundreds to thousands of pruritic, dome-shaped, follicular papules with or without central keratin plugs. Ectropion, mucosal lesions, and masklike facies are other clinical characteristics of Grzybowski syndrome. Ferguson-Smith disease begins in the second decade of life. The eruption of multiple keratoacanthomas and/or squamous cell carcinomas occurs in crops, rapidly growing over 2 to 4 weeks, and then self-resolves. This disease is inherited in an autosomal-dominant manner and is associated with chromosome 9q22. Keratosis pilaris is a benign condition of follicular hyperkeratosis that can appear in any age group and usually is absent of symptoms. It is not associated with any systemic disease. Clinically, the condition appears as folliculocentric keratotic papules with varying degrees of perifollicular erythema located along the extensor surfaces. Keratosis pilaris and APDRD share features of a follicular hyperkeratosis and dilated infundibulum; however, perforation is absent in keratosis pilaris. Lastly, prurigo nodularis is another intensely pruritic dermatosis associated with renal disease that presents as papulonodules on the extensor surfaces of the arms and legs. A biopsy can help to distinguish prurigo nodularis from APDRD.

THE DIAGNOSIS:

Acquired Perforating Disorder of Renal Disease

A papule with the central plug removed left a pitlike depression, representing Kyrle disease (Figure 1). A punch biopsy of the left forearm revealed epidermal hyperplasia (Figure 2A) surrounding a keratin plug that contained degenerated basophilic material (Figure 2B), confirming the diagnosis of acquired perforating disorder of renal disease (APDRD), classically described as Kyrle disease.

Acquired perforating disorder of renal disease is an uncommon condition in the general population. It is associated with systemic disease, commonly diabetes mellitus and chronic renal failure, and is seen in up to 10% patients receiving hemodialysis.¹ The underlying etiology and pathogenesis of APDRD remains unknown. It has been proposed to be a variant of prurigo nodularis, representing end-stage excoriated folliculitis.¹ Given that most cases appear in patients with systemic disease and metabolic abnormalities, APDRD also has been classified under the spectrum of acquired perforating dermatoses, a group of disorders defined by transepithelial elimination of dermal connective tissue. Elevated levels of serum and tissue fibronectin, uremia, and hyperphosphatemia have been observed in patients with APDRD.^1,2 Fibronectin stimulates epithelial migration and proliferation and may lead to expulsion of keratin. Furthermore, dermal deposition of excess urea and/or phosphate could initiate transepithelial elimination of material. Alternative hypotheses implicate abnormal keratinization or an imbalance between the rates of epidermal proliferation/ differentiation and keratin production, whereby keratin production outpaces the former. Keratin deposited within the dermis subsequently elicits an inflammatory response along with alterations in the local dermis and connective tissue. These components become intermixed and are extruded through the plug opening.³ Lastly, immune dysregulation resulting from systemic disease could contribute to APDRD through increased expression of IL-31, a cytokine thought to play a role in several pruritic inflammatory skin diseases.⁴

Although standardized treatment guidelines for APDRD have not been established, the mainstay of therapy is control of the underlying systemic disorder. Intense pruritus and repeated scratching may contribute to microtrauma and subsequent koebnerization of new lesions.³ Thus, ameliorating pruritus can provide both symptomatic relief and prevent the development of new lesions. Retinoids, UV light, oral antibiotics, antihistamines, corticosteroids, keratolytic agents, and immunosuppressants (eg, allopurinol, tacrolimus) have shown some benefit.⁴

The differential diagnoses for APDRD include arthropod hypersensitivity reactions, eruptive keratoacanthomas, keratosis pilaris, and prurigo nodularis. Arthropod hypersensitivity reactions are seen in patients with a history of a bite or sting from arthropods such as bees, fleas, mites, ticks, and spiders. These reactions cause symptoms of pain, burning, or pruritus and present heterogeneously. They can be edematous and appear as single or multiple papules, pustules, plaques, vesicles, and/or bullae. A central punctum or crusting also may be present. Eruptive keratoacanthomas are seen in Grzybowski syndrome and Ferguson-Smith disease. Grzybowski syndrome arises in the fifth to seventh decades of life and is characterized by the eruptive onset of hundreds to thousands of pruritic, dome-shaped, follicular papules with or without central keratin plugs. Ectropion, mucosal lesions, and masklike facies are other clinical characteristics of Grzybowski syndrome. Ferguson-Smith disease begins in the second decade of life. The eruption of multiple keratoacanthomas and/or squamous cell carcinomas occurs in crops, rapidly growing over 2 to 4 weeks, and then self-resolves. This disease is inherited in an autosomal-dominant manner and is associated with chromosome 9q22. Keratosis pilaris is a benign condition of follicular hyperkeratosis that can appear in any age group and usually is absent of symptoms. It is not associated with any systemic disease. Clinically, the condition appears as folliculocentric keratotic papules with varying degrees of perifollicular erythema located along the extensor surfaces. Keratosis pilaris and APDRD share features of a follicular hyperkeratosis and dilated infundibulum; however, perforation is absent in keratosis pilaris. Lastly, prurigo nodularis is another intensely pruritic dermatosis associated with renal disease that presents as papulonodules on the extensor surfaces of the arms and legs. A biopsy can help to distinguish prurigo nodularis from APDRD.

THE DIAGNOSIS:

Acquired Perforating Disorder of Renal Disease

A papule with the central plug removed left a pitlike depression, representing Kyrle disease (Figure 1). A punch biopsy of the left forearm revealed epidermal hyperplasia (Figure 2A) surrounding a keratin plug that contained degenerated basophilic material (Figure 2B), confirming the diagnosis of acquired perforating disorder of renal disease (APDRD), classically described as Kyrle disease.

Acquired perforating disorder of renal disease is an uncommon condition in the general population. It is associated with systemic disease, commonly diabetes mellitus and chronic renal failure, and is seen in up to 10% patients receiving hemodialysis.¹ The underlying etiology and pathogenesis of APDRD remains unknown. It has been proposed to be a variant of prurigo nodularis, representing end-stage excoriated folliculitis.¹ Given that most cases appear in patients with systemic disease and metabolic abnormalities, APDRD also has been classified under the spectrum of acquired perforating dermatoses, a group of disorders defined by transepithelial elimination of dermal connective tissue. Elevated levels of serum and tissue fibronectin, uremia, and hyperphosphatemia have been observed in patients with APDRD.^1,2 Fibronectin stimulates epithelial migration and proliferation and may lead to expulsion of keratin. Furthermore, dermal deposition of excess urea and/or phosphate could initiate transepithelial elimination of material. Alternative hypotheses implicate abnormal keratinization or an imbalance between the rates of epidermal proliferation/ differentiation and keratin production, whereby keratin production outpaces the former. Keratin deposited within the dermis subsequently elicits an inflammatory response along with alterations in the local dermis and connective tissue. These components become intermixed and are extruded through the plug opening.³ Lastly, immune dysregulation resulting from systemic disease could contribute to APDRD through increased expression of IL-31, a cytokine thought to play a role in several pruritic inflammatory skin diseases.⁴

Although standardized treatment guidelines for APDRD have not been established, the mainstay of therapy is control of the underlying systemic disorder. Intense pruritus and repeated scratching may contribute to microtrauma and subsequent koebnerization of new lesions.³ Thus, ameliorating pruritus can provide both symptomatic relief and prevent the development of new lesions. Retinoids, UV light, oral antibiotics, antihistamines, corticosteroids, keratolytic agents, and immunosuppressants (eg, allopurinol, tacrolimus) have shown some benefit.⁴

The differential diagnoses for APDRD include arthropod hypersensitivity reactions, eruptive keratoacanthomas, keratosis pilaris, and prurigo nodularis. Arthropod hypersensitivity reactions are seen in patients with a history of a bite or sting from arthropods such as bees, fleas, mites, ticks, and spiders. These reactions cause symptoms of pain, burning, or pruritus and present heterogeneously. They can be edematous and appear as single or multiple papules, pustules, plaques, vesicles, and/or bullae. A central punctum or crusting also may be present. Eruptive keratoacanthomas are seen in Grzybowski syndrome and Ferguson-Smith disease. Grzybowski syndrome arises in the fifth to seventh decades of life and is characterized by the eruptive onset of hundreds to thousands of pruritic, dome-shaped, follicular papules with or without central keratin plugs. Ectropion, mucosal lesions, and masklike facies are other clinical characteristics of Grzybowski syndrome. Ferguson-Smith disease begins in the second decade of life. The eruption of multiple keratoacanthomas and/or squamous cell carcinomas occurs in crops, rapidly growing over 2 to 4 weeks, and then self-resolves. This disease is inherited in an autosomal-dominant manner and is associated with chromosome 9q22. Keratosis pilaris is a benign condition of follicular hyperkeratosis that can appear in any age group and usually is absent of symptoms. It is not associated with any systemic disease. Clinically, the condition appears as folliculocentric keratotic papules with varying degrees of perifollicular erythema located along the extensor surfaces. Keratosis pilaris and APDRD share features of a follicular hyperkeratosis and dilated infundibulum; however, perforation is absent in keratosis pilaris. Lastly, prurigo nodularis is another intensely pruritic dermatosis associated with renal disease that presents as papulonodules on the extensor surfaces of the arms and legs. A biopsy can help to distinguish prurigo nodularis from APDRD.

THE DIAGNOSIS:

Cutaneous Metastatic Mesothelioma

Biopsies of the larger erythematous papules revealed an infiltrate of atypical tumor cells with mitoses (Figure 1) that were immunoreactive for calretinin (Figure 2) and lacked nuclear BRCA1 associated protein-1, BAP1, expression (not shown). The patient’s prior mesothelioma was re-reviewed, and the cutaneous tumor cells were similar to the primary mesothelioma. A diagnosis of cutaneous metastatic mesothelioma (CMM) was made.

Mesothelioma is a rare neoplasm arising from the pleura, pericardium, peritoneum, and tunica vaginalis,¹ with an estimated annual incidence of 2500 cases.² The predominant risk factor for the development of pleural mesothelioma is asbestos exposure, which has been identified in up to 90% of cases. Mesothelioma can give rise to local and less frequently distant hematogenous metastases. Cutaneous involvement of mesothelioma is rare.³ More than 80% of CMM cases are attributed to seeding the skin at procedure sites or by direct infiltration of scars. Distant CMM is rare and typically presents as subcutaneous nodules.⁴ Few cases of inflammatory CMM have been published,^1,4,5 with even fewer mimicking herpes zoster infection (HZI), as seen in our patient.

The most specific stain for mesothelioma is calretinin, which strongly and diffusely stains both the nucleus and cytoplasm. Other markers include Wilms tumor 1, cytokeratin 5/6, thrombomodulin, and HBME-1. Immunohistochemistry to detect the loss of BAP1 staining in the nucleus is important for differentiating between mesothelioma and mesothelial hyperplasia.³

Cutaneous metastases occur in 0.7% to 9% of patients with internal malignant disease. Most commonly, cutaneous metastases present as cutaneous nodules, though other reported inflammatory presentations include erysipeloides, generalized erythematous patches, telangiectasia, and zosteriform distributions.⁶ Zosteriform distributions are particularly rare and most commonly are due to breast carcinomas or lymphomas. The mechanism of zosteriform metastasis is unknown, but theories include tumoral spread along vessels, invasion of the thoracic perineural sheaths, localized spread of tumor cells from a surgical site, or a Koebner-like reaction at the site of an existing HZI. Regardless of primary tumor type or presentation, cutaneous metastasis is a poor prognostic sign, with survival rates varying based on primary tumor type.⁷

Other differential diagnoses include herpes zoster granulomatous dermatitis, radiation recall dermatitis, cutaneous Rosai-Dorfman disease, and zosteriform lichen planus, all of which have been reported after HZI.^8-10 Herpes zoster granulomatous dermatitis typically presents weeks to years after acute HZI with erythematous to violaceous papules and plaques at the site of the prior HZI. A biopsy reveals interstitial granulomatous dermatitis and multinucleated giant cells.⁸ Radiation recall dermatitis is a cutaneous inflammatory reaction limited to regions of prior radiation exposure after the administration of a triggering medication. Radiation recall dermatitis can present days to many years after the completion of treatment.⁹ Although the eruption in our patient was at the site of prior radiation, the pathologic and clinical presentation was not consistent with radiation recall dermatitis. Cutaneous Rosai-Dorfman disease is a non-Langerhans cell histiocytosis that may present as either solitary or numerous papules, plaques, or nodules and has been reported to occur after HZI. Biopsy reveals a diffuse dermal histiocytic infiltration with plasma cells and lymphocytes. In contrast to metastatic disease, mitoses and nuclear atypia are rare in cutaneous RosaiDorfman disease.¹¹ Lichen planus is an inflammatory disease of unknown etiology presenting as flat-topped, violaceous, pruritic papules¹² that may present in a zosteriform pattern.¹³

Although it is uncommon, metastatic spread should be considered in patients with known malignancy presenting with zosteriform eruptions.² Our patient remained on treatment with immunotherapy, as he was unable to undergo additional radiation and had failed multiple other lines of therapy. He died 3 months after presentation.

THE DIAGNOSIS:

Cutaneous Metastatic Mesothelioma

Biopsies of the larger erythematous papules revealed an infiltrate of atypical tumor cells with mitoses (Figure 1) that were immunoreactive for calretinin (Figure 2) and lacked nuclear BRCA1 associated protein-1, BAP1, expression (not shown). The patient’s prior mesothelioma was re-reviewed, and the cutaneous tumor cells were similar to the primary mesothelioma. A diagnosis of cutaneous metastatic mesothelioma (CMM) was made.

Mesothelioma is a rare neoplasm arising from the pleura, pericardium, peritoneum, and tunica vaginalis,¹ with an estimated annual incidence of 2500 cases.² The predominant risk factor for the development of pleural mesothelioma is asbestos exposure, which has been identified in up to 90% of cases. Mesothelioma can give rise to local and less frequently distant hematogenous metastases. Cutaneous involvement of mesothelioma is rare.³ More than 80% of CMM cases are attributed to seeding the skin at procedure sites or by direct infiltration of scars. Distant CMM is rare and typically presents as subcutaneous nodules.⁴ Few cases of inflammatory CMM have been published,^1,4,5 with even fewer mimicking herpes zoster infection (HZI), as seen in our patient.

The most specific stain for mesothelioma is calretinin, which strongly and diffusely stains both the nucleus and cytoplasm. Other markers include Wilms tumor 1, cytokeratin 5/6, thrombomodulin, and HBME-1. Immunohistochemistry to detect the loss of BAP1 staining in the nucleus is important for differentiating between mesothelioma and mesothelial hyperplasia.³

Cutaneous metastases occur in 0.7% to 9% of patients with internal malignant disease. Most commonly, cutaneous metastases present as cutaneous nodules, though other reported inflammatory presentations include erysipeloides, generalized erythematous patches, telangiectasia, and zosteriform distributions.⁶ Zosteriform distributions are particularly rare and most commonly are due to breast carcinomas or lymphomas. The mechanism of zosteriform metastasis is unknown, but theories include tumoral spread along vessels, invasion of the thoracic perineural sheaths, localized spread of tumor cells from a surgical site, or a Koebner-like reaction at the site of an existing HZI. Regardless of primary tumor type or presentation, cutaneous metastasis is a poor prognostic sign, with survival rates varying based on primary tumor type.⁷

Other differential diagnoses include herpes zoster granulomatous dermatitis, radiation recall dermatitis, cutaneous Rosai-Dorfman disease, and zosteriform lichen planus, all of which have been reported after HZI.^8-10 Herpes zoster granulomatous dermatitis typically presents weeks to years after acute HZI with erythematous to violaceous papules and plaques at the site of the prior HZI. A biopsy reveals interstitial granulomatous dermatitis and multinucleated giant cells.⁸ Radiation recall dermatitis is a cutaneous inflammatory reaction limited to regions of prior radiation exposure after the administration of a triggering medication. Radiation recall dermatitis can present days to many years after the completion of treatment.⁹ Although the eruption in our patient was at the site of prior radiation, the pathologic and clinical presentation was not consistent with radiation recall dermatitis. Cutaneous Rosai-Dorfman disease is a non-Langerhans cell histiocytosis that may present as either solitary or numerous papules, plaques, or nodules and has been reported to occur after HZI. Biopsy reveals a diffuse dermal histiocytic infiltration with plasma cells and lymphocytes. In contrast to metastatic disease, mitoses and nuclear atypia are rare in cutaneous RosaiDorfman disease.¹¹ Lichen planus is an inflammatory disease of unknown etiology presenting as flat-topped, violaceous, pruritic papules¹² that may present in a zosteriform pattern.¹³

Although it is uncommon, metastatic spread should be considered in patients with known malignancy presenting with zosteriform eruptions.² Our patient remained on treatment with immunotherapy, as he was unable to undergo additional radiation and had failed multiple other lines of therapy. He died 3 months after presentation.

THE DIAGNOSIS:

Cutaneous Metastatic Mesothelioma

Biopsies of the larger erythematous papules revealed an infiltrate of atypical tumor cells with mitoses (Figure 1) that were immunoreactive for calretinin (Figure 2) and lacked nuclear BRCA1 associated protein-1, BAP1, expression (not shown). The patient’s prior mesothelioma was re-reviewed, and the cutaneous tumor cells were similar to the primary mesothelioma. A diagnosis of cutaneous metastatic mesothelioma (CMM) was made.

Mesothelioma is a rare neoplasm arising from the pleura, pericardium, peritoneum, and tunica vaginalis,¹ with an estimated annual incidence of 2500 cases.² The predominant risk factor for the development of pleural mesothelioma is asbestos exposure, which has been identified in up to 90% of cases. Mesothelioma can give rise to local and less frequently distant hematogenous metastases. Cutaneous involvement of mesothelioma is rare.³ More than 80% of CMM cases are attributed to seeding the skin at procedure sites or by direct infiltration of scars. Distant CMM is rare and typically presents as subcutaneous nodules.⁴ Few cases of inflammatory CMM have been published,^1,4,5 with even fewer mimicking herpes zoster infection (HZI), as seen in our patient.

The most specific stain for mesothelioma is calretinin, which strongly and diffusely stains both the nucleus and cytoplasm. Other markers include Wilms tumor 1, cytokeratin 5/6, thrombomodulin, and HBME-1. Immunohistochemistry to detect the loss of BAP1 staining in the nucleus is important for differentiating between mesothelioma and mesothelial hyperplasia.³

Cutaneous metastases occur in 0.7% to 9% of patients with internal malignant disease. Most commonly, cutaneous metastases present as cutaneous nodules, though other reported inflammatory presentations include erysipeloides, generalized erythematous patches, telangiectasia, and zosteriform distributions.⁶ Zosteriform distributions are particularly rare and most commonly are due to breast carcinomas or lymphomas. The mechanism of zosteriform metastasis is unknown, but theories include tumoral spread along vessels, invasion of the thoracic perineural sheaths, localized spread of tumor cells from a surgical site, or a Koebner-like reaction at the site of an existing HZI. Regardless of primary tumor type or presentation, cutaneous metastasis is a poor prognostic sign, with survival rates varying based on primary tumor type.⁷

Other differential diagnoses include herpes zoster granulomatous dermatitis, radiation recall dermatitis, cutaneous Rosai-Dorfman disease, and zosteriform lichen planus, all of which have been reported after HZI.^8-10 Herpes zoster granulomatous dermatitis typically presents weeks to years after acute HZI with erythematous to violaceous papules and plaques at the site of the prior HZI. A biopsy reveals interstitial granulomatous dermatitis and multinucleated giant cells.⁸ Radiation recall dermatitis is a cutaneous inflammatory reaction limited to regions of prior radiation exposure after the administration of a triggering medication. Radiation recall dermatitis can present days to many years after the completion of treatment.⁹ Although the eruption in our patient was at the site of prior radiation, the pathologic and clinical presentation was not consistent with radiation recall dermatitis. Cutaneous Rosai-Dorfman disease is a non-Langerhans cell histiocytosis that may present as either solitary or numerous papules, plaques, or nodules and has been reported to occur after HZI. Biopsy reveals a diffuse dermal histiocytic infiltration with plasma cells and lymphocytes. In contrast to metastatic disease, mitoses and nuclear atypia are rare in cutaneous RosaiDorfman disease.¹¹ Lichen planus is an inflammatory disease of unknown etiology presenting as flat-topped, violaceous, pruritic papules¹² that may present in a zosteriform pattern.¹³

Although it is uncommon, metastatic spread should be considered in patients with known malignancy presenting with zosteriform eruptions.² Our patient remained on treatment with immunotherapy, as he was unable to undergo additional radiation and had failed multiple other lines of therapy. He died 3 months after presentation.

THE DIAGNOSIS: Vegetative Majocchi Granuloma

A biopsy and tissue culture showed acute dermal inflammation with granulomatous features and numerous fungal hyphae within the stratum corneum (Figure 1A), which were confirmed on GrocottGomori methenamine-silver staining (Figure 1B). Gram and Fite stains were negative for bacteria. A tissue culture speciated Trichophyton rubrum, which led to a diagnosis of deep dermatophyte infection (Majocchi granuloma) with a highly unusual clinical presentation of vegetative plaques. Predisposing factors included treatment with topical corticosteroids and possibly poor health and nutritional status at baseline. Our patient was treated with fluconazole 200 mg daily for 6 weeks, with near resolution of lesions at 3-week follow-up (Figure 2).

Dermatophytes are a common cause of superficial skin infections. The classic morphology consists of an annular scaly plaque; however, a wide variety of presentations have been observed (eg, verrucous, vesicular, pustular, granulomatous). Therefore, dermatophyte infections often mimic other dermatologic conditions, including atopic dermatitis, rosacea, psoriasis, bacterial abscess, erythema gyratum repens, lupus, granuloma annulare, cutaneous lymphoma, Hailey-Hailey disease, scarring alopecia, and syphilis.¹

Notably, when dermatophytes grow downward along hair follicles causing deeper infection, disruption of the follicular wall can lead to an excessive inflammatory response with granulomatous features.² Risk factors include cutaneous trauma, long-standing infection, immunocompromise, and treatment with topical corticosteroids.³ This disease evolution clinically appears as a nodule or infiltrated plaque, often without scale. The most well-known example is a kerion on the scalp. Elsewhere on the body, lesions often are termed Majocchi granulomas.²

Vegetative plaques, as seen in our patient, are a highly unusual morphology for deep tinea infection. Guanziroli et al⁴ reported a case of vegetative lesions on the forearm of a 67-year-old immunocompromised man that were successfully treated with a 3-month course of oral terbinafine after Trichophyton verrucosum was isolated. Skorepova et al⁵ reported a case of pyoderma vegetans triggered by recurrent Trichophyton mentagrophytes on the dorsal hands of a 64-year-old man with immunoglobulin deficiency of unknown etiology. The lesions were successfully treated with a prolonged course of doxycycline, topical triamcinolone, and intravenous immunoglobulin following 2 initial courses of terbinafine.

The differential diagnosis for vegetative lesions includes pemphigus vegetans, a vegetative variant of pyoderma gangrenosum; halogenoderma; and a variety of infections, including dimorphic fungi (histoplasmosis, blastomycosis), blastomycosislike pyoderma (bacterial), and candidiasis.⁶ These conditions usually can be distinguished based on histopathology. Clinically, pemphigus vegetans presents with pustules and vegetative lesions, as in our patient, but usually is more diffuse and favors the intertriginous areas. Histology likely would reveal foci of acantholysis and eosinophils. Vegetative pyoderma gangrenosum favors the trunk, particularly in sites of surgical trauma. In our patient, no lesions were present near the abdominal surgical sites, and there was no antecedent cribriform ulceration. Halogenoderma was a strong initial consideration given the localization, presence of large pustules, and history of numerous contrast computed tomography studies; however, our patient’s iodine levels were normal. Infectious etiologies including dimorphic fungi and blastomycosislike pyoderma generally are not restricted to the head and neck, and tissue culture helps exclude them. Vegetative lesions may occur in the setting of other infections, and tissue culture may be necessary to differentiate them if histopathology is not suggestive.

Deep dermatophyte infections require treatment with oral antifungals, as topicals do not penetrate adequately into the hair follicles. Exact regimens vary, but generally oral terbinafine or an oral azole (except ketoconazole) is administered for 2 to 6 weeks, with immunocompromise necessitating longer courses.

We present a rare case of vegetative Majocchi granuloma secondary to T rubrum infection. A dermatophyte infection should be included in the differential for vegetative lesions, especially in dense hair-bearing areas such as the beard. Treatment generally is straightforward with oral antifungals.

THE DIAGNOSIS: Vegetative Majocchi Granuloma

A biopsy and tissue culture showed acute dermal inflammation with granulomatous features and numerous fungal hyphae within the stratum corneum (Figure 1A), which were confirmed on GrocottGomori methenamine-silver staining (Figure 1B). Gram and Fite stains were negative for bacteria. A tissue culture speciated Trichophyton rubrum, which led to a diagnosis of deep dermatophyte infection (Majocchi granuloma) with a highly unusual clinical presentation of vegetative plaques. Predisposing factors included treatment with topical corticosteroids and possibly poor health and nutritional status at baseline. Our patient was treated with fluconazole 200 mg daily for 6 weeks, with near resolution of lesions at 3-week follow-up (Figure 2).

Dermatophytes are a common cause of superficial skin infections. The classic morphology consists of an annular scaly plaque; however, a wide variety of presentations have been observed (eg, verrucous, vesicular, pustular, granulomatous). Therefore, dermatophyte infections often mimic other dermatologic conditions, including atopic dermatitis, rosacea, psoriasis, bacterial abscess, erythema gyratum repens, lupus, granuloma annulare, cutaneous lymphoma, Hailey-Hailey disease, scarring alopecia, and syphilis.¹

Notably, when dermatophytes grow downward along hair follicles causing deeper infection, disruption of the follicular wall can lead to an excessive inflammatory response with granulomatous features.² Risk factors include cutaneous trauma, long-standing infection, immunocompromise, and treatment with topical corticosteroids.³ This disease evolution clinically appears as a nodule or infiltrated plaque, often without scale. The most well-known example is a kerion on the scalp. Elsewhere on the body, lesions often are termed Majocchi granulomas.²

Vegetative plaques, as seen in our patient, are a highly unusual morphology for deep tinea infection. Guanziroli et al⁴ reported a case of vegetative lesions on the forearm of a 67-year-old immunocompromised man that were successfully treated with a 3-month course of oral terbinafine after Trichophyton verrucosum was isolated. Skorepova et al⁵ reported a case of pyoderma vegetans triggered by recurrent Trichophyton mentagrophytes on the dorsal hands of a 64-year-old man with immunoglobulin deficiency of unknown etiology. The lesions were successfully treated with a prolonged course of doxycycline, topical triamcinolone, and intravenous immunoglobulin following 2 initial courses of terbinafine.

The differential diagnosis for vegetative lesions includes pemphigus vegetans, a vegetative variant of pyoderma gangrenosum; halogenoderma; and a variety of infections, including dimorphic fungi (histoplasmosis, blastomycosis), blastomycosislike pyoderma (bacterial), and candidiasis.⁶ These conditions usually can be distinguished based on histopathology. Clinically, pemphigus vegetans presents with pustules and vegetative lesions, as in our patient, but usually is more diffuse and favors the intertriginous areas. Histology likely would reveal foci of acantholysis and eosinophils. Vegetative pyoderma gangrenosum favors the trunk, particularly in sites of surgical trauma. In our patient, no lesions were present near the abdominal surgical sites, and there was no antecedent cribriform ulceration. Halogenoderma was a strong initial consideration given the localization, presence of large pustules, and history of numerous contrast computed tomography studies; however, our patient’s iodine levels were normal. Infectious etiologies including dimorphic fungi and blastomycosislike pyoderma generally are not restricted to the head and neck, and tissue culture helps exclude them. Vegetative lesions may occur in the setting of other infections, and tissue culture may be necessary to differentiate them if histopathology is not suggestive.

Deep dermatophyte infections require treatment with oral antifungals, as topicals do not penetrate adequately into the hair follicles. Exact regimens vary, but generally oral terbinafine or an oral azole (except ketoconazole) is administered for 2 to 6 weeks, with immunocompromise necessitating longer courses.

We present a rare case of vegetative Majocchi granuloma secondary to T rubrum infection. A dermatophyte infection should be included in the differential for vegetative lesions, especially in dense hair-bearing areas such as the beard. Treatment generally is straightforward with oral antifungals.

THE DIAGNOSIS: Vegetative Majocchi Granuloma

A biopsy and tissue culture showed acute dermal inflammation with granulomatous features and numerous fungal hyphae within the stratum corneum (Figure 1A), which were confirmed on GrocottGomori methenamine-silver staining (Figure 1B). Gram and Fite stains were negative for bacteria. A tissue culture speciated Trichophyton rubrum, which led to a diagnosis of deep dermatophyte infection (Majocchi granuloma) with a highly unusual clinical presentation of vegetative plaques. Predisposing factors included treatment with topical corticosteroids and possibly poor health and nutritional status at baseline. Our patient was treated with fluconazole 200 mg daily for 6 weeks, with near resolution of lesions at 3-week follow-up (Figure 2).

Dermatophytes are a common cause of superficial skin infections. The classic morphology consists of an annular scaly plaque; however, a wide variety of presentations have been observed (eg, verrucous, vesicular, pustular, granulomatous). Therefore, dermatophyte infections often mimic other dermatologic conditions, including atopic dermatitis, rosacea, psoriasis, bacterial abscess, erythema gyratum repens, lupus, granuloma annulare, cutaneous lymphoma, Hailey-Hailey disease, scarring alopecia, and syphilis.¹

Notably, when dermatophytes grow downward along hair follicles causing deeper infection, disruption of the follicular wall can lead to an excessive inflammatory response with granulomatous features.² Risk factors include cutaneous trauma, long-standing infection, immunocompromise, and treatment with topical corticosteroids.³ This disease evolution clinically appears as a nodule or infiltrated plaque, often without scale. The most well-known example is a kerion on the scalp. Elsewhere on the body, lesions often are termed Majocchi granulomas.²

Vegetative plaques, as seen in our patient, are a highly unusual morphology for deep tinea infection. Guanziroli et al⁴ reported a case of vegetative lesions on the forearm of a 67-year-old immunocompromised man that were successfully treated with a 3-month course of oral terbinafine after Trichophyton verrucosum was isolated. Skorepova et al⁵ reported a case of pyoderma vegetans triggered by recurrent Trichophyton mentagrophytes on the dorsal hands of a 64-year-old man with immunoglobulin deficiency of unknown etiology. The lesions were successfully treated with a prolonged course of doxycycline, topical triamcinolone, and intravenous immunoglobulin following 2 initial courses of terbinafine.

The differential diagnosis for vegetative lesions includes pemphigus vegetans, a vegetative variant of pyoderma gangrenosum; halogenoderma; and a variety of infections, including dimorphic fungi (histoplasmosis, blastomycosis), blastomycosislike pyoderma (bacterial), and candidiasis.⁶ These conditions usually can be distinguished based on histopathology. Clinically, pemphigus vegetans presents with pustules and vegetative lesions, as in our patient, but usually is more diffuse and favors the intertriginous areas. Histology likely would reveal foci of acantholysis and eosinophils. Vegetative pyoderma gangrenosum favors the trunk, particularly in sites of surgical trauma. In our patient, no lesions were present near the abdominal surgical sites, and there was no antecedent cribriform ulceration. Halogenoderma was a strong initial consideration given the localization, presence of large pustules, and history of numerous contrast computed tomography studies; however, our patient’s iodine levels were normal. Infectious etiologies including dimorphic fungi and blastomycosislike pyoderma generally are not restricted to the head and neck, and tissue culture helps exclude them. Vegetative lesions may occur in the setting of other infections, and tissue culture may be necessary to differentiate them if histopathology is not suggestive.

Deep dermatophyte infections require treatment with oral antifungals, as topicals do not penetrate adequately into the hair follicles. Exact regimens vary, but generally oral terbinafine or an oral azole (except ketoconazole) is administered for 2 to 6 weeks, with immunocompromise necessitating longer courses.

We present a rare case of vegetative Majocchi granuloma secondary to T rubrum infection. A dermatophyte infection should be included in the differential for vegetative lesions, especially in dense hair-bearing areas such as the beard. Treatment generally is straightforward with oral antifungals.

The Diagnosis: Multicentric Reticulohistiocytosis

Te patient presented with pink papules coalescing into plaques on the upper chest and lower back (Figure 1) as well as a characteristic finding of periungual papules with a coral bead appearance. Histopathologic examination revealed a dense infiltrate of epithelioid histiocytes with amphophilic ground-glass cytoplasm in a nodular configuration (Figure 2). This pattern in conjunction with the clinical features seen in our patient was consistent with a diagnosis of multicentric reticulohistiocytosis (MRH).^1-3 The cutaneous symptoms were managed with triamcinolone ointment 0.1% twice daily and oral hydroxyzine 10 mg 3 times daily as needed for itching with moderate improvement. She was referred to rheumatology for arthritis management, and the initial cancer screening was negative.

Multicentric reticulohistiocytosis is a rare granulomatous disease characterized by papulonodular cutaneous lesions and severe erosive arthritis. It has an insidious onset and most commonly affects middle-aged women.¹ Multicentric reticulohistiocytosis typically presents as rounded pruritic papules or nodules that may be pink, red, or brown primarily affecting the face and distal upper extremities.^1,3 Mucosal involvement occurs in more than half of patients and is characterized by multiple erythematous papules and nodules on the oral and nasopharyngeal mucosae that rarely can produce leonine facies.² A hallmark feature of MRH is the presence of multiple shiny erythematous papules along the proximal and lateral nail folds that take on a coral bead appearance.^1,3,4 Furthermore, nail changes such as atrophy, longitudinal ridging, brittleness, and hyperpigmentation can occur secondary to a synovial reaction that disturbs the nail matrix.^4,5

Joint involvement precedes cutaneous involvement in most cases of MRH.^1,5 Multicentric reticulohistiocytosis is associated with a symmetric destructive arthritis affecting the hands, knees, shoulders, and hips that often is associated with pain, stiffness, and swelling.^1,3 The arthritis rapidly progresses in the early stages of the disease but then becomes less active over the subsequent 8 to 10 years.¹ It has the potential to develop into arthritis mutilans, an end-stage form of arthritis also seen in psoriatic and rheumatoid arthritis that leads to severe joint deformity and debilitation.^1,2

The etiology of MRH still is unknown, but it has an association with underlying malignancy in up to 25% of patients.⁶ Multicentric reticulohistiocytosis has been reported in the context of a wide variety of malignancies including melanoma; sarcoma; lymphoma; leukemia; and carcinomas of the breast, colon, and lung. In some cases, the diagnosis of MRH may even precede the diagnosis of cancer.³ Multicentric reticulohistiocytosis also may be associated with autoimmune conditions,³ as seen in our patient who had a history of both hypothyroidism and vitiligo.

Histopathologic examination is essential in distinguishing MRH from other autoimmune disorders associated with hand lesions, rash, and arthralgia. Erythema elevatum diutinum is associated with symmetric, violaceous, red or brown papules and plaques located on the extensor surfaces of the extremities and hands; however, histology reveals a leukocytoclastic vasculitis with a mixture of polymorphonuclear leukocytes and lymphocytes.⁷ Dermatomyositis may present with arthralgia, flattopped, erythematous (Gottron) papules localized over the proximal interphalangeal and distal interphalangeal joints, as well as proximal nail findings. The latter generally presents with periungual erythema associated with dilated capillary loops rather than the discrete orderly papules seen in MRH. Histologic examination of dermatomyositis shows mild epidermal atrophy, vacuolar changes in the basal keratinocyte layer, and a dermal perivascular lymphocytic infiltrate.⁸ Because MRH initially can present with joint symptoms and hand nodules, it may be confused with rheumatoid arthritis. However, rheumatoid arthritis typically is associated with severe osteopenia and tends to affect the metacarpophalangeal and proximal interphalangeal joints rather than the distal interphalangeal joints that most often are affected in MRH.¹ Histologic examination of rheumatoid nodules reveals palisading granulomas surrounding a central area of fibrinoid necrosis.⁹ Sarcoidosis is a multisystem disease that can present with cutaneous involvement including erythema nodosum, skin plaques, subcutaneous nodules, and papular eruptions in addition to joint lesions.¹⁰ Sarcoidosis most frequently involves the lungs, manifesting as diffuse interstitial lung disease with bilateral hilar lymphadenopathy. Furthermore, histologic examination of lesions demonstrates classic noncaseating granulomas containing epithelioid cells, multinucleated giant cells with inclusion bodies, and lymphocytes.¹¹

A skin biopsy is required to establish the diagnosis of MRH. In general, patients with MRH and no underlying malignancy have a good prognosis and respond to anti-inflammatory therapies such as nonsteroidal antiinflammatory drugs and corticosteroids. Other agents including methotrexate, cyclophosphamide, and tumor necrosis factor α inhibitors also have been effective in more severe cases.^1,3,12 Finally, in addition to treating the cutaneous manifestations of MRH, it is important to screen patients for underlying malignancies and other autoimmune conditions.

The Diagnosis: Multicentric Reticulohistiocytosis

Te patient presented with pink papules coalescing into plaques on the upper chest and lower back (Figure 1) as well as a characteristic finding of periungual papules with a coral bead appearance. Histopathologic examination revealed a dense infiltrate of epithelioid histiocytes with amphophilic ground-glass cytoplasm in a nodular configuration (Figure 2). This pattern in conjunction with the clinical features seen in our patient was consistent with a diagnosis of multicentric reticulohistiocytosis (MRH).^1-3 The cutaneous symptoms were managed with triamcinolone ointment 0.1% twice daily and oral hydroxyzine 10 mg 3 times daily as needed for itching with moderate improvement. She was referred to rheumatology for arthritis management, and the initial cancer screening was negative.

Multicentric reticulohistiocytosis is a rare granulomatous disease characterized by papulonodular cutaneous lesions and severe erosive arthritis. It has an insidious onset and most commonly affects middle-aged women.¹ Multicentric reticulohistiocytosis typically presents as rounded pruritic papules or nodules that may be pink, red, or brown primarily affecting the face and distal upper extremities.^1,3 Mucosal involvement occurs in more than half of patients and is characterized by multiple erythematous papules and nodules on the oral and nasopharyngeal mucosae that rarely can produce leonine facies.² A hallmark feature of MRH is the presence of multiple shiny erythematous papules along the proximal and lateral nail folds that take on a coral bead appearance.^1,3,4 Furthermore, nail changes such as atrophy, longitudinal ridging, brittleness, and hyperpigmentation can occur secondary to a synovial reaction that disturbs the nail matrix.^4,5

Joint involvement precedes cutaneous involvement in most cases of MRH.^1,5 Multicentric reticulohistiocytosis is associated with a symmetric destructive arthritis affecting the hands, knees, shoulders, and hips that often is associated with pain, stiffness, and swelling.^1,3 The arthritis rapidly progresses in the early stages of the disease but then becomes less active over the subsequent 8 to 10 years.¹ It has the potential to develop into arthritis mutilans, an end-stage form of arthritis also seen in psoriatic and rheumatoid arthritis that leads to severe joint deformity and debilitation.^1,2

The etiology of MRH still is unknown, but it has an association with underlying malignancy in up to 25% of patients.⁶ Multicentric reticulohistiocytosis has been reported in the context of a wide variety of malignancies including melanoma; sarcoma; lymphoma; leukemia; and carcinomas of the breast, colon, and lung. In some cases, the diagnosis of MRH may even precede the diagnosis of cancer.³ Multicentric reticulohistiocytosis also may be associated with autoimmune conditions,³ as seen in our patient who had a history of both hypothyroidism and vitiligo.

Histopathologic examination is essential in distinguishing MRH from other autoimmune disorders associated with hand lesions, rash, and arthralgia. Erythema elevatum diutinum is associated with symmetric, violaceous, red or brown papules and plaques located on the extensor surfaces of the extremities and hands; however, histology reveals a leukocytoclastic vasculitis with a mixture of polymorphonuclear leukocytes and lymphocytes.⁷ Dermatomyositis may present with arthralgia, flattopped, erythematous (Gottron) papules localized over the proximal interphalangeal and distal interphalangeal joints, as well as proximal nail findings. The latter generally presents with periungual erythema associated with dilated capillary loops rather than the discrete orderly papules seen in MRH. Histologic examination of dermatomyositis shows mild epidermal atrophy, vacuolar changes in the basal keratinocyte layer, and a dermal perivascular lymphocytic infiltrate.⁸ Because MRH initially can present with joint symptoms and hand nodules, it may be confused with rheumatoid arthritis. However, rheumatoid arthritis typically is associated with severe osteopenia and tends to affect the metacarpophalangeal and proximal interphalangeal joints rather than the distal interphalangeal joints that most often are affected in MRH.¹ Histologic examination of rheumatoid nodules reveals palisading granulomas surrounding a central area of fibrinoid necrosis.⁹ Sarcoidosis is a multisystem disease that can present with cutaneous involvement including erythema nodosum, skin plaques, subcutaneous nodules, and papular eruptions in addition to joint lesions.¹⁰ Sarcoidosis most frequently involves the lungs, manifesting as diffuse interstitial lung disease with bilateral hilar lymphadenopathy. Furthermore, histologic examination of lesions demonstrates classic noncaseating granulomas containing epithelioid cells, multinucleated giant cells with inclusion bodies, and lymphocytes.¹¹

A skin biopsy is required to establish the diagnosis of MRH. In general, patients with MRH and no underlying malignancy have a good prognosis and respond to anti-inflammatory therapies such as nonsteroidal antiinflammatory drugs and corticosteroids. Other agents including methotrexate, cyclophosphamide, and tumor necrosis factor α inhibitors also have been effective in more severe cases.^1,3,12 Finally, in addition to treating the cutaneous manifestations of MRH, it is important to screen patients for underlying malignancies and other autoimmune conditions.

The Diagnosis: Multicentric Reticulohistiocytosis

Te patient presented with pink papules coalescing into plaques on the upper chest and lower back (Figure 1) as well as a characteristic finding of periungual papules with a coral bead appearance. Histopathologic examination revealed a dense infiltrate of epithelioid histiocytes with amphophilic ground-glass cytoplasm in a nodular configuration (Figure 2). This pattern in conjunction with the clinical features seen in our patient was consistent with a diagnosis of multicentric reticulohistiocytosis (MRH).^1-3 The cutaneous symptoms were managed with triamcinolone ointment 0.1% twice daily and oral hydroxyzine 10 mg 3 times daily as needed for itching with moderate improvement. She was referred to rheumatology for arthritis management, and the initial cancer screening was negative.

Multicentric reticulohistiocytosis is a rare granulomatous disease characterized by papulonodular cutaneous lesions and severe erosive arthritis. It has an insidious onset and most commonly affects middle-aged women.¹ Multicentric reticulohistiocytosis typically presents as rounded pruritic papules or nodules that may be pink, red, or brown primarily affecting the face and distal upper extremities.^1,3 Mucosal involvement occurs in more than half of patients and is characterized by multiple erythematous papules and nodules on the oral and nasopharyngeal mucosae that rarely can produce leonine facies.² A hallmark feature of MRH is the presence of multiple shiny erythematous papules along the proximal and lateral nail folds that take on a coral bead appearance.^1,3,4 Furthermore, nail changes such as atrophy, longitudinal ridging, brittleness, and hyperpigmentation can occur secondary to a synovial reaction that disturbs the nail matrix.^4,5

Joint involvement precedes cutaneous involvement in most cases of MRH.^1,5 Multicentric reticulohistiocytosis is associated with a symmetric destructive arthritis affecting the hands, knees, shoulders, and hips that often is associated with pain, stiffness, and swelling.^1,3 The arthritis rapidly progresses in the early stages of the disease but then becomes less active over the subsequent 8 to 10 years.¹ It has the potential to develop into arthritis mutilans, an end-stage form of arthritis also seen in psoriatic and rheumatoid arthritis that leads to severe joint deformity and debilitation.^1,2

The etiology of MRH still is unknown, but it has an association with underlying malignancy in up to 25% of patients.⁶ Multicentric reticulohistiocytosis has been reported in the context of a wide variety of malignancies including melanoma; sarcoma; lymphoma; leukemia; and carcinomas of the breast, colon, and lung. In some cases, the diagnosis of MRH may even precede the diagnosis of cancer.³ Multicentric reticulohistiocytosis also may be associated with autoimmune conditions,³ as seen in our patient who had a history of both hypothyroidism and vitiligo.

Histopathologic examination is essential in distinguishing MRH from other autoimmune disorders associated with hand lesions, rash, and arthralgia. Erythema elevatum diutinum is associated with symmetric, violaceous, red or brown papules and plaques located on the extensor surfaces of the extremities and hands; however, histology reveals a leukocytoclastic vasculitis with a mixture of polymorphonuclear leukocytes and lymphocytes.⁷ Dermatomyositis may present with arthralgia, flattopped, erythematous (Gottron) papules localized over the proximal interphalangeal and distal interphalangeal joints, as well as proximal nail findings. The latter generally presents with periungual erythema associated with dilated capillary loops rather than the discrete orderly papules seen in MRH. Histologic examination of dermatomyositis shows mild epidermal atrophy, vacuolar changes in the basal keratinocyte layer, and a dermal perivascular lymphocytic infiltrate.⁸ Because MRH initially can present with joint symptoms and hand nodules, it may be confused with rheumatoid arthritis. However, rheumatoid arthritis typically is associated with severe osteopenia and tends to affect the metacarpophalangeal and proximal interphalangeal joints rather than the distal interphalangeal joints that most often are affected in MRH.¹ Histologic examination of rheumatoid nodules reveals palisading granulomas surrounding a central area of fibrinoid necrosis.⁹ Sarcoidosis is a multisystem disease that can present with cutaneous involvement including erythema nodosum, skin plaques, subcutaneous nodules, and papular eruptions in addition to joint lesions.¹⁰ Sarcoidosis most frequently involves the lungs, manifesting as diffuse interstitial lung disease with bilateral hilar lymphadenopathy. Furthermore, histologic examination of lesions demonstrates classic noncaseating granulomas containing epithelioid cells, multinucleated giant cells with inclusion bodies, and lymphocytes.¹¹

A skin biopsy is required to establish the diagnosis of MRH. In general, patients with MRH and no underlying malignancy have a good prognosis and respond to anti-inflammatory therapies such as nonsteroidal antiinflammatory drugs and corticosteroids. Other agents including methotrexate, cyclophosphamide, and tumor necrosis factor α inhibitors also have been effective in more severe cases.^1,3,12 Finally, in addition to treating the cutaneous manifestations of MRH, it is important to screen patients for underlying malignancies and other autoimmune conditions.

The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.^1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.² Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.²

Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.² Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.² Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.^2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.

Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.¹ Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.¹

Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.^2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.^2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.⁵

The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.⁶ In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.⁶ Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.⁷ Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.²

The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.^1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.² Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.²

Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.² Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.² Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.^2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.

Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.¹ Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.¹

Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.^2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.^2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.⁵

The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.⁶ In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.⁶ Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.⁷ Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.²

The Diagnosis: Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal-dominant disorder that increases the risk for developing various carcinomas and affects multiple organ systems. Nevoid basal cell carcinoma syndrome is estimated at 1 per 40,000 to 60,000 individuals with no sexual predilection.^1,2 Pathogenesis of NBCCS occurs through molecular alterations in the dormant hedgehog signaling pathway, causing constitutive signaling activity and a loss of function in the tumor suppressor patched 1 gene, PTCH1. As a result, the inhibition of smoothened oncogenes is released, Gli proteins are activated, and the hedgehog signaling pathway is no longer quiescent.² Additional loss of function in the suppressor of fused homolog protein, a negative regulator of the hedgehog pathway, allows for further tumor proliferation. The crucial role these genes play in the hedgehog signaling pathway and their mutation association with NBCCS allows for molecular confirmation in the diagnosis of NBCCS. Allelic losses at the PTCH1 gene site are thought to occur in approximately 70% of NBCCS patients.²

Diagnosis of NBCCS is based on genetic testing to examine pathogenic gene variants, notably in the PTCH1 gene, and identification of characteristic clinical findings.² Diagnosis of NBCCS requires either 2 minor suggestive criteria and 1 major suggestive criterion, 2 major suggestive criteria and 1 minor suggestive criterion, or 1 major suggestive criterion with molecular confirmation. The presence of basal cell carcinomas (BCCs) before 20 years of age or an excessive numbers of BCCs, keratocystic odontogenic tumors (KOTs), palmar or plantar pitting, and first-degree relatives with NBCCS are classified as major suggestive criteria.² Nevoid basal cell carcinoma syndrome patients typically have BCCs that crust, ulcerate, or bleed. Minor suggestive criteria for NBCCS are rib abnormalities, skeletal malformations, macrocephaly, cleft lip or palate, and desmoplastic medulloblastoma.^2-4 Suppressor of fused homolog protein mutations may increase the risk for desmoplastic medulloblastoma in NBCCS patients. Our patient had 4 of the major suggestive criteria, including a history of KOTs, multiple BCCs, first-degree relatives with NBCCS, and palmar or plantar pitting (bottom quiz image), while having 1 minor suggestive criterion of frontal bossing.

Patients with NBCCS have high phenotypic variability, as their skin carcinomas do not have the classic features of pearly surfaces or corkscrew telangiectasia that typically are associated with BCCs.¹ Basal cell carcinomas in NBCCS-affected individuals usually are indistinguishable from sporadic lesions that arise in sun-exposed areas, making NBCCS difficult to diagnose. These sporadic lesions often are misdiagnosed as psoriatic or eczematous lesions, and additional subsequent examination is required. The findings of multiple papules and plaques spanning the body as well as lesions with rolled borders and ulcerated bases, indicative of BCCs, aid dermatologists in distinguishing benign lesions from those of NBCCS.¹

Additional differential diagnoses are required to distinguish NBCCS from other similar inherited skin disorders that are characterized by BCCs. The presence of multiple incidental BCCs early in life remains a histopathologic clue for NBCCS diagnosis, as opposed to Rombo syndrome, in which BCCs often develop in adulthood.^2,4 In addition, although both Bazex syndrome and Muir-Torre syndrome are characterized by the early onset of BCCs, the lack of skeletal abnormalities and palmar and plantar pitting distinguish these entities from NBCCS.^2,4 Furthermore, though psoriasis also can present on the scalp, clinical presentation often includes well-demarcated and symmetric plaques that are erythematous and silvery, all of which were not present in our patient and typically are not seen in NBCCS.⁵

The recommended treatment of NBCCS is vismodegib, a specific oncogene inhibitor. This medication suppresses the hedgehog signaling pathway by inhibiting smoothened oncogenes and downstream target molecules, thereby decreasing tumor proliferation.⁶ In doing so, vismodegib inhibits the development of new BCCs while reducing the burden of present ones. Additionally, vismodegib appears to effectively treat KOTs. If successful, this medication may be able to suppress KOTs in patients with NBCCS and thus facilitate surgery.⁶ Additional hedgehog inhibitors include patidegib, sonidegib, and itraconazole. Patidegib gel 2% currently is in phase 3 clinical trials for evaluation of efficacy and safety in treatment of NBCCS. Sonidegib is approved for the treatment of locally advanced BCCs in the United States and the European Union and for both locally advanced BCCs and metastatic BCCs in Switzerland and Australia.⁷ Further research is needed before recommending antifungal itraconazole for NBCCS clinical use.8 Other medications for localized areas include topical application of 5-fluorouracil and imiquimod.²

The Diagnosis: Vibrio vulnificus Infection

At the initial presentation, the differential diagnosis included infectious processes such as bacterial or angioinvasive fungal infections or an inflammatory process such as pyoderma gangrenosum. Blood cultures were found to be positive for pansensitive Vibrio vulnificus. He initially was treated with piperacillin-tazobactam and received surgical debridement of the affected tissues. Pathologic interpretation of the wound tissues revealed a diagnosis of necrotizing softtissue infection and positive Candida albicans growth. He received topical bacitracin on discharge as well as a 7-day course of amoxicillin-clavulanate and fluconazole. He continued to receive debridement procedures and skin grafts, followed by topical mupirocin treatment and silver sulfadiazine. He was seen 6 weeks after discharge with healing wounds and healthy-appearing granulation tissue at the base.

Our patient’s presentation of retiform purpura with stellate necrosis was consistent with a wide range of serious pathologies ranging from medium-vessel vasculitis to thromboembolic phenomena and angioinvasive fungal infections.¹ Although Vibrio infection rarely is the first explanation that comes to mind when observing necrotic retiform purpura, the chronic nonhealing injury on the leg combined with the recent history of ocean swimming made V vulnificus stand out as a likely culprit. Although V vulnificus infection traditionally presents with cellulitis, edema, and hemorrhagic bulla,² necrosis also has been observed.³Vibrio vulnificus produces multiple virulence factors, and it is believed that these severe cutaneous symptoms are attributable to the production of a specific metalloprotease that enhances vascular permeability, thereby inducing hemorrhage within the vascular basement membrane zone.²

Vibrio vulnificus is an opportunistic bacterial pathogen associated with consumption of contaminated seafood or swimming in ocean waters with open wounds. Infections are rare, with only approximately 100 cases reported annually in the United States.4 However, V vulnificus infections have demonstrated increasing incidence in recent years, especially infections of pre-existing wounds.^4,5 Risk factors for their development include age over 40 years and underlying conditions including liver disease, diabetes mellitus, and immune dysfunction.⁴Vibrio vulnificus infections also demonstrate a strong male predilection, with almost 90% of infections occurring in males.⁴ Although the precise etiology of this sex discrepancy remains unknown, estrogen has been suggested to be a protective factor.⁶ Alternatively, behavioral differences also have been proposed as possible explanations for this discrepancy, with women less likely to consume seafood or go swimming. However, epidemiologic data reveal strong correlations between male sex and liver cirrhosis, a primary risk factor for V vulnificus infections, suggesting that male sex may simply be a confounding variable.⁷

Infections with V vulnificus are notable for their short incubation periods, with onset of symptoms occurring within 24 hours of exposure, making prompt diagnosis and treatment of high importance.⁸ Although rare, V vulnificus infections are associated with high mortality rates. From 1988 to 2010, nearly 600 deaths were reported secondary to V vulnificus infections.⁴ Wound infections carry a 17.6% fatality rate,⁴ while bloodborne V vulnificus infections exceed 50% fatality.⁸ Although sepsis secondary to V vulnificus usually is caused by ingestion of raw or undercooked shellfish, primarily oysters,⁴ our case highlights a rarer instance of both sepsis and localized infection stemming from ocean water exposure.

Vibrio vulnificus is an obligate halophile and therefore is found in marine environments rather than freshwater bodies. However, it rarely is isolated from bodies of water with salinities over 25 parts per thousand, such as the Mediterranean Sea; it usually is found in warmer waters, making it more common in the summer months from May to October.⁴ Given this proclivity for warmer environments, climate change has contributed to both a greater incidence and global distribution of V vulnificus. ^9,10

Treatment of V vulnificus infections centers on antibiotic treatment, with Vibrio species generally demonstrating susceptibility to most antibiotics of human significance.¹¹ However, some Vibrio isolates within the United States have demonstrated antibiotic resistance; 45% of a variety of clinical and environmental samples from South Carolina and Georgia demonstrated resistance to at least 3 antibiotic classes, and 17.3% resisted 8 or more classes of antibiotics.¹² These included medications such as doxycycline, tetracycline, aminoglycosides, and cephalosporins—agents that normally are prescribed for V vulnificus infections. Although tetracyclines have long been touted as the preferred treatment of V vulnificus infections, the spread of antibiotic resistance may require greater reliance on alternative regimens such as combinations of cephalosporins and doxycycline or a single fluoroquinolone.¹³ Although rare, Vibrio infections can have rapidly fatal consequences and should be given serious consideration when evaluating patients with relevant risk factors.

The differential diagnosis included angioinvasive mucormycosis, calciphylaxis, pyoderma gangrenosum, and Stevens-Johnson syndrome/toxic epidermal necrolysis. Mucormycosis is a fungal infection caused by Mucorales fungi that most commonly is seen in patients with diabetes mellitus, hematologic malignancies, neutropenia, and immunocompromise.¹⁴ Calciphylaxis is a condition involving microvascular occlusion due to diffuse calcium deposition in cutaneous blood vessels. It typically presents as violaceous retiform patches and plaques commonly seen on areas such as the thighs, buttocks, or abdomen and usually is associated with chronic renal failure, hemodialysis, and/or secondary hyperparathyroidism.¹⁵ Pyoderma gangrenosum is an inflammatory condition involving neutrophilic ulceration of the skin that typically presents as ulceration with a classically undermined border. It frequently is considered a diagnosis of exclusion and therefore requires that providers rule out other causes of ulceration prior to diagnosis.¹⁶ Stevens-Johnson syndrome/toxic epidermal necrolysis is a rare drug reaction involving mucosal erosions and cutaneous detachment.¹⁷ This diagnosis is less likely given that our patient lacked mucosal involvement and did not have any notable medication exposures prior to symptom onset.

The Diagnosis: Vibrio vulnificus Infection

At the initial presentation, the differential diagnosis included infectious processes such as bacterial or angioinvasive fungal infections or an inflammatory process such as pyoderma gangrenosum. Blood cultures were found to be positive for pansensitive Vibrio vulnificus. He initially was treated with piperacillin-tazobactam and received surgical debridement of the affected tissues. Pathologic interpretation of the wound tissues revealed a diagnosis of necrotizing softtissue infection and positive Candida albicans growth. He received topical bacitracin on discharge as well as a 7-day course of amoxicillin-clavulanate and fluconazole. He continued to receive debridement procedures and skin grafts, followed by topical mupirocin treatment and silver sulfadiazine. He was seen 6 weeks after discharge with healing wounds and healthy-appearing granulation tissue at the base.

Our patient’s presentation of retiform purpura with stellate necrosis was consistent with a wide range of serious pathologies ranging from medium-vessel vasculitis to thromboembolic phenomena and angioinvasive fungal infections.¹ Although Vibrio infection rarely is the first explanation that comes to mind when observing necrotic retiform purpura, the chronic nonhealing injury on the leg combined with the recent history of ocean swimming made V vulnificus stand out as a likely culprit. Although V vulnificus infection traditionally presents with cellulitis, edema, and hemorrhagic bulla,² necrosis also has been observed.³Vibrio vulnificus produces multiple virulence factors, and it is believed that these severe cutaneous symptoms are attributable to the production of a specific metalloprotease that enhances vascular permeability, thereby inducing hemorrhage within the vascular basement membrane zone.²

Vibrio vulnificus is an opportunistic bacterial pathogen associated with consumption of contaminated seafood or swimming in ocean waters with open wounds. Infections are rare, with only approximately 100 cases reported annually in the United States.4 However, V vulnificus infections have demonstrated increasing incidence in recent years, especially infections of pre-existing wounds.^4,5 Risk factors for their development include age over 40 years and underlying conditions including liver disease, diabetes mellitus, and immune dysfunction.⁴Vibrio vulnificus infections also demonstrate a strong male predilection, with almost 90% of infections occurring in males.⁴ Although the precise etiology of this sex discrepancy remains unknown, estrogen has been suggested to be a protective factor.⁶ Alternatively, behavioral differences also have been proposed as possible explanations for this discrepancy, with women less likely to consume seafood or go swimming. However, epidemiologic data reveal strong correlations between male sex and liver cirrhosis, a primary risk factor for V vulnificus infections, suggesting that male sex may simply be a confounding variable.⁷

Infections with V vulnificus are notable for their short incubation periods, with onset of symptoms occurring within 24 hours of exposure, making prompt diagnosis and treatment of high importance.⁸ Although rare, V vulnificus infections are associated with high mortality rates. From 1988 to 2010, nearly 600 deaths were reported secondary to V vulnificus infections.⁴ Wound infections carry a 17.6% fatality rate,⁴ while bloodborne V vulnificus infections exceed 50% fatality.⁸ Although sepsis secondary to V vulnificus usually is caused by ingestion of raw or undercooked shellfish, primarily oysters,⁴ our case highlights a rarer instance of both sepsis and localized infection stemming from ocean water exposure.

Vibrio vulnificus is an obligate halophile and therefore is found in marine environments rather than freshwater bodies. However, it rarely is isolated from bodies of water with salinities over 25 parts per thousand, such as the Mediterranean Sea; it usually is found in warmer waters, making it more common in the summer months from May to October.⁴ Given this proclivity for warmer environments, climate change has contributed to both a greater incidence and global distribution of V vulnificus. ^9,10

Treatment of V vulnificus infections centers on antibiotic treatment, with Vibrio species generally demonstrating susceptibility to most antibiotics of human significance.¹¹ However, some Vibrio isolates within the United States have demonstrated antibiotic resistance; 45% of a variety of clinical and environmental samples from South Carolina and Georgia demonstrated resistance to at least 3 antibiotic classes, and 17.3% resisted 8 or more classes of antibiotics.¹² These included medications such as doxycycline, tetracycline, aminoglycosides, and cephalosporins—agents that normally are prescribed for V vulnificus infections. Although tetracyclines have long been touted as the preferred treatment of V vulnificus infections, the spread of antibiotic resistance may require greater reliance on alternative regimens such as combinations of cephalosporins and doxycycline or a single fluoroquinolone.¹³ Although rare, Vibrio infections can have rapidly fatal consequences and should be given serious consideration when evaluating patients with relevant risk factors.

The differential diagnosis included angioinvasive mucormycosis, calciphylaxis, pyoderma gangrenosum, and Stevens-Johnson syndrome/toxic epidermal necrolysis. Mucormycosis is a fungal infection caused by Mucorales fungi that most commonly is seen in patients with diabetes mellitus, hematologic malignancies, neutropenia, and immunocompromise.¹⁴ Calciphylaxis is a condition involving microvascular occlusion due to diffuse calcium deposition in cutaneous blood vessels. It typically presents as violaceous retiform patches and plaques commonly seen on areas such as the thighs, buttocks, or abdomen and usually is associated with chronic renal failure, hemodialysis, and/or secondary hyperparathyroidism.¹⁵ Pyoderma gangrenosum is an inflammatory condition involving neutrophilic ulceration of the skin that typically presents as ulceration with a classically undermined border. It frequently is considered a diagnosis of exclusion and therefore requires that providers rule out other causes of ulceration prior to diagnosis.¹⁶ Stevens-Johnson syndrome/toxic epidermal necrolysis is a rare drug reaction involving mucosal erosions and cutaneous detachment.¹⁷ This diagnosis is less likely given that our patient lacked mucosal involvement and did not have any notable medication exposures prior to symptom onset.

The Diagnosis: Vibrio vulnificus Infection

At the initial presentation, the differential diagnosis included infectious processes such as bacterial or angioinvasive fungal infections or an inflammatory process such as pyoderma gangrenosum. Blood cultures were found to be positive for pansensitive Vibrio vulnificus. He initially was treated with piperacillin-tazobactam and received surgical debridement of the affected tissues. Pathologic interpretation of the wound tissues revealed a diagnosis of necrotizing softtissue infection and positive Candida albicans growth. He received topical bacitracin on discharge as well as a 7-day course of amoxicillin-clavulanate and fluconazole. He continued to receive debridement procedures and skin grafts, followed by topical mupirocin treatment and silver sulfadiazine. He was seen 6 weeks after discharge with healing wounds and healthy-appearing granulation tissue at the base.

Our patient’s presentation of retiform purpura with stellate necrosis was consistent with a wide range of serious pathologies ranging from medium-vessel vasculitis to thromboembolic phenomena and angioinvasive fungal infections.¹ Although Vibrio infection rarely is the first explanation that comes to mind when observing necrotic retiform purpura, the chronic nonhealing injury on the leg combined with the recent history of ocean swimming made V vulnificus stand out as a likely culprit. Although V vulnificus infection traditionally presents with cellulitis, edema, and hemorrhagic bulla,² necrosis also has been observed.³Vibrio vulnificus produces multiple virulence factors, and it is believed that these severe cutaneous symptoms are attributable to the production of a specific metalloprotease that enhances vascular permeability, thereby inducing hemorrhage within the vascular basement membrane zone.²

Vibrio vulnificus is an opportunistic bacterial pathogen associated with consumption of contaminated seafood or swimming in ocean waters with open wounds. Infections are rare, with only approximately 100 cases reported annually in the United States.4 However, V vulnificus infections have demonstrated increasing incidence in recent years, especially infections of pre-existing wounds.^4,5 Risk factors for their development include age over 40 years and underlying conditions including liver disease, diabetes mellitus, and immune dysfunction.⁴Vibrio vulnificus infections also demonstrate a strong male predilection, with almost 90% of infections occurring in males.⁴ Although the precise etiology of this sex discrepancy remains unknown, estrogen has been suggested to be a protective factor.⁶ Alternatively, behavioral differences also have been proposed as possible explanations for this discrepancy, with women less likely to consume seafood or go swimming. However, epidemiologic data reveal strong correlations between male sex and liver cirrhosis, a primary risk factor for V vulnificus infections, suggesting that male sex may simply be a confounding variable.⁷

Infections with V vulnificus are notable for their short incubation periods, with onset of symptoms occurring within 24 hours of exposure, making prompt diagnosis and treatment of high importance.⁸ Although rare, V vulnificus infections are associated with high mortality rates. From 1988 to 2010, nearly 600 deaths were reported secondary to V vulnificus infections.⁴ Wound infections carry a 17.6% fatality rate,⁴ while bloodborne V vulnificus infections exceed 50% fatality.⁸ Although sepsis secondary to V vulnificus usually is caused by ingestion of raw or undercooked shellfish, primarily oysters,⁴ our case highlights a rarer instance of both sepsis and localized infection stemming from ocean water exposure.

Vibrio vulnificus is an obligate halophile and therefore is found in marine environments rather than freshwater bodies. However, it rarely is isolated from bodies of water with salinities over 25 parts per thousand, such as the Mediterranean Sea; it usually is found in warmer waters, making it more common in the summer months from May to October.⁴ Given this proclivity for warmer environments, climate change has contributed to both a greater incidence and global distribution of V vulnificus. ^9,10

Treatment of V vulnificus infections centers on antibiotic treatment, with Vibrio species generally demonstrating susceptibility to most antibiotics of human significance.¹¹ However, some Vibrio isolates within the United States have demonstrated antibiotic resistance; 45% of a variety of clinical and environmental samples from South Carolina and Georgia demonstrated resistance to at least 3 antibiotic classes, and 17.3% resisted 8 or more classes of antibiotics.¹² These included medications such as doxycycline, tetracycline, aminoglycosides, and cephalosporins—agents that normally are prescribed for V vulnificus infections. Although tetracyclines have long been touted as the preferred treatment of V vulnificus infections, the spread of antibiotic resistance may require greater reliance on alternative regimens such as combinations of cephalosporins and doxycycline or a single fluoroquinolone.¹³ Although rare, Vibrio infections can have rapidly fatal consequences and should be given serious consideration when evaluating patients with relevant risk factors.

The differential diagnosis included angioinvasive mucormycosis, calciphylaxis, pyoderma gangrenosum, and Stevens-Johnson syndrome/toxic epidermal necrolysis. Mucormycosis is a fungal infection caused by Mucorales fungi that most commonly is seen in patients with diabetes mellitus, hematologic malignancies, neutropenia, and immunocompromise.¹⁴ Calciphylaxis is a condition involving microvascular occlusion due to diffuse calcium deposition in cutaneous blood vessels. It typically presents as violaceous retiform patches and plaques commonly seen on areas such as the thighs, buttocks, or abdomen and usually is associated with chronic renal failure, hemodialysis, and/or secondary hyperparathyroidism.¹⁵ Pyoderma gangrenosum is an inflammatory condition involving neutrophilic ulceration of the skin that typically presents as ulceration with a classically undermined border. It frequently is considered a diagnosis of exclusion and therefore requires that providers rule out other causes of ulceration prior to diagnosis.¹⁶ Stevens-Johnson syndrome/toxic epidermal necrolysis is a rare drug reaction involving mucosal erosions and cutaneous detachment.¹⁷ This diagnosis is less likely given that our patient lacked mucosal involvement and did not have any notable medication exposures prior to symptom onset.

The Diagnosis: Osteoma Cutis

Osteoma cutis is the heterotopic development of cutaneous ossifications in the dermis or subcutaneous fat and presents as plaquelike, stony, hard nodules. It can manifest as either a primary or secondary condition based on the presence or absence of a prior skin insult at the lesion site. Primary osteoma cutis occurs in 15% of patients and arises either de novo or in association with any of several inflammatory, neoplastic, and metabolic diseases that provide a favorable environment for abnormal mesenchymal stem cell commitment to osteoid,¹ including Albright hereditary osteodystrophy, myositis ossificans progressiva, and progressive osseous heteroplasia, which are all associated with mutations in the heterotrimeric G-protein alpha subunit encoding gene, GNAS. ^1,2 It is suggested that an insufficiency of Gsα leads to uncontrolled negative regulation of nonosseous connective tissue differentiation, forming osteoid.³ Additionally, diseases involving gain-of-function mutations in the activin A receptor type 1 encoding gene, ACVR1, such as fibrodysplasia ossificans progressiva, have been associated with osteoma cutis.⁴ These mutations lead to decreased receptor affinity to molecular safeguards of bone morphogenetic protein signaling, ultimately contributing to progressive ectopic bone formation.⁵ Secondary osteoma cutis occurs in 85% of patients and develops at the site of prior skin damage due to inflammation, neoplasm, or trauma.⁶ It is believed that tissue damage and degeneration lead to mesenchymal stem cell proliferation and skeletogenicinducing factor recruitment forming cartilaginous tissue, later replaced by bone through endochondral ossification.⁷

Although osteoma cutis previously was believed to be rare, more recent radiologic studies suggest otherwise, detecting cutaneous osteomas in up to 42.1% of patients.⁸ Consequently, it is likely that osteoma cutis is underdiagnosed due to its subclinical nature. Our patient, however, presented with a solitary osteoma cutis with perforation of the epidermis, a rare phenomenon.^9-12

A shave biopsy in our patient revealed moderate to focally marked, irregular epidermal hyperplasia with a large focus of moderate, compact, parakeratotic crust overlying the epidermis in the center of the specimen. The papillary dermis in the center of the specimen revealed large foci of dark pink to purple bone fragments surrounded by moderate lymphocytic infiltrate with few foci perforating through the overlying epidermis (Figure, A). These findings were characteristic of osteoma cutis with perforation through the overlying epidermis.

The diagnosis of osteoma cutis at the age of 62 years suggested that the lesion was not primary in association with previously described diseases. Furthermore, the lack of phenotypic features of these diseases including obesity, developmental disability, and high parathyroid hormone levels essentially excluded this possibility. The presence of the lesion on the lower extremities initially may have suggested osteoma cutis secondary to chronic venous insufficiency¹³; however, the absence of visible varicose veins or obvious signs of stasis disease made this unlikely. No further cutaneous disorders at or around the lesion site clinically and histologically suggested that our patient’s lesion was primary and of idiopathic nature. Dermatofibroma can present similarly in appearance but would characteristically dimple centrally when pinched. Keratoacanthoma presents with central ulceration and keratin plugging. Pilomatricoma more commonly presents on the head and neck and less frequently as a firm nodule. Lastly, prurigo nodularis more commonly presents as a symmetrically diffuse rash compared to an isolated nodule.

Osteoma cutis is a cutaneous ossification that may be primary or secondary in nature and less rare than originally thought. Workup for potentially associated inflammatory, neoplastic, and metabolic diseases should be considered in patients with this condition. Perforating osteoma cutis is a rare variant that presents as solitary or multiple nodules with central erosion and crust. The mechanism of transepidermal elimination leading to skin perforation is hypothesized to involve epidermal hyperproliferation leading to upward movement.¹⁴ Shave biopsy establishes a definitive histopathologic diagnosis and often is curative. Given that lesions of osteoma cutis themselves are benign, removal may not be necessary.

The Diagnosis: Osteoma Cutis

Osteoma cutis is the heterotopic development of cutaneous ossifications in the dermis or subcutaneous fat and presents as plaquelike, stony, hard nodules. It can manifest as either a primary or secondary condition based on the presence or absence of a prior skin insult at the lesion site. Primary osteoma cutis occurs in 15% of patients and arises either de novo or in association with any of several inflammatory, neoplastic, and metabolic diseases that provide a favorable environment for abnormal mesenchymal stem cell commitment to osteoid,¹ including Albright hereditary osteodystrophy, myositis ossificans progressiva, and progressive osseous heteroplasia, which are all associated with mutations in the heterotrimeric G-protein alpha subunit encoding gene, GNAS. ^1,2 It is suggested that an insufficiency of Gsα leads to uncontrolled negative regulation of nonosseous connective tissue differentiation, forming osteoid.³ Additionally, diseases involving gain-of-function mutations in the activin A receptor type 1 encoding gene, ACVR1, such as fibrodysplasia ossificans progressiva, have been associated with osteoma cutis.⁴ These mutations lead to decreased receptor affinity to molecular safeguards of bone morphogenetic protein signaling, ultimately contributing to progressive ectopic bone formation.⁵ Secondary osteoma cutis occurs in 85% of patients and develops at the site of prior skin damage due to inflammation, neoplasm, or trauma.⁶ It is believed that tissue damage and degeneration lead to mesenchymal stem cell proliferation and skeletogenicinducing factor recruitment forming cartilaginous tissue, later replaced by bone through endochondral ossification.⁷

Although osteoma cutis previously was believed to be rare, more recent radiologic studies suggest otherwise, detecting cutaneous osteomas in up to 42.1% of patients.⁸ Consequently, it is likely that osteoma cutis is underdiagnosed due to its subclinical nature. Our patient, however, presented with a solitary osteoma cutis with perforation of the epidermis, a rare phenomenon.^9-12

A shave biopsy in our patient revealed moderate to focally marked, irregular epidermal hyperplasia with a large focus of moderate, compact, parakeratotic crust overlying the epidermis in the center of the specimen. The papillary dermis in the center of the specimen revealed large foci of dark pink to purple bone fragments surrounded by moderate lymphocytic infiltrate with few foci perforating through the overlying epidermis (Figure, A). These findings were characteristic of osteoma cutis with perforation through the overlying epidermis.

The diagnosis of osteoma cutis at the age of 62 years suggested that the lesion was not primary in association with previously described diseases. Furthermore, the lack of phenotypic features of these diseases including obesity, developmental disability, and high parathyroid hormone levels essentially excluded this possibility. The presence of the lesion on the lower extremities initially may have suggested osteoma cutis secondary to chronic venous insufficiency¹³; however, the absence of visible varicose veins or obvious signs of stasis disease made this unlikely. No further cutaneous disorders at or around the lesion site clinically and histologically suggested that our patient’s lesion was primary and of idiopathic nature. Dermatofibroma can present similarly in appearance but would characteristically dimple centrally when pinched. Keratoacanthoma presents with central ulceration and keratin plugging. Pilomatricoma more commonly presents on the head and neck and less frequently as a firm nodule. Lastly, prurigo nodularis more commonly presents as a symmetrically diffuse rash compared to an isolated nodule.

Osteoma cutis is a cutaneous ossification that may be primary or secondary in nature and less rare than originally thought. Workup for potentially associated inflammatory, neoplastic, and metabolic diseases should be considered in patients with this condition. Perforating osteoma cutis is a rare variant that presents as solitary or multiple nodules with central erosion and crust. The mechanism of transepidermal elimination leading to skin perforation is hypothesized to involve epidermal hyperproliferation leading to upward movement.¹⁴ Shave biopsy establishes a definitive histopathologic diagnosis and often is curative. Given that lesions of osteoma cutis themselves are benign, removal may not be necessary.

The Diagnosis: Osteoma Cutis

Osteoma cutis is the heterotopic development of cutaneous ossifications in the dermis or subcutaneous fat and presents as plaquelike, stony, hard nodules. It can manifest as either a primary or secondary condition based on the presence or absence of a prior skin insult at the lesion site. Primary osteoma cutis occurs in 15% of patients and arises either de novo or in association with any of several inflammatory, neoplastic, and metabolic diseases that provide a favorable environment for abnormal mesenchymal stem cell commitment to osteoid,¹ including Albright hereditary osteodystrophy, myositis ossificans progressiva, and progressive osseous heteroplasia, which are all associated with mutations in the heterotrimeric G-protein alpha subunit encoding gene, GNAS. ^1,2 It is suggested that an insufficiency of Gsα leads to uncontrolled negative regulation of nonosseous connective tissue differentiation, forming osteoid.³ Additionally, diseases involving gain-of-function mutations in the activin A receptor type 1 encoding gene, ACVR1, such as fibrodysplasia ossificans progressiva, have been associated with osteoma cutis.⁴ These mutations lead to decreased receptor affinity to molecular safeguards of bone morphogenetic protein signaling, ultimately contributing to progressive ectopic bone formation.⁵ Secondary osteoma cutis occurs in 85% of patients and develops at the site of prior skin damage due to inflammation, neoplasm, or trauma.⁶ It is believed that tissue damage and degeneration lead to mesenchymal stem cell proliferation and skeletogenicinducing factor recruitment forming cartilaginous tissue, later replaced by bone through endochondral ossification.⁷

Although osteoma cutis previously was believed to be rare, more recent radiologic studies suggest otherwise, detecting cutaneous osteomas in up to 42.1% of patients.⁸ Consequently, it is likely that osteoma cutis is underdiagnosed due to its subclinical nature. Our patient, however, presented with a solitary osteoma cutis with perforation of the epidermis, a rare phenomenon.^9-12

A shave biopsy in our patient revealed moderate to focally marked, irregular epidermal hyperplasia with a large focus of moderate, compact, parakeratotic crust overlying the epidermis in the center of the specimen. The papillary dermis in the center of the specimen revealed large foci of dark pink to purple bone fragments surrounded by moderate lymphocytic infiltrate with few foci perforating through the overlying epidermis (Figure, A). These findings were characteristic of osteoma cutis with perforation through the overlying epidermis.

The diagnosis of osteoma cutis at the age of 62 years suggested that the lesion was not primary in association with previously described diseases. Furthermore, the lack of phenotypic features of these diseases including obesity, developmental disability, and high parathyroid hormone levels essentially excluded this possibility. The presence of the lesion on the lower extremities initially may have suggested osteoma cutis secondary to chronic venous insufficiency¹³; however, the absence of visible varicose veins or obvious signs of stasis disease made this unlikely. No further cutaneous disorders at or around the lesion site clinically and histologically suggested that our patient’s lesion was primary and of idiopathic nature. Dermatofibroma can present similarly in appearance but would characteristically dimple centrally when pinched. Keratoacanthoma presents with central ulceration and keratin plugging. Pilomatricoma more commonly presents on the head and neck and less frequently as a firm nodule. Lastly, prurigo nodularis more commonly presents as a symmetrically diffuse rash compared to an isolated nodule.

Osteoma cutis is a cutaneous ossification that may be primary or secondary in nature and less rare than originally thought. Workup for potentially associated inflammatory, neoplastic, and metabolic diseases should be considered in patients with this condition. Perforating osteoma cutis is a rare variant that presents as solitary or multiple nodules with central erosion and crust. The mechanism of transepidermal elimination leading to skin perforation is hypothesized to involve epidermal hyperproliferation leading to upward movement.¹⁴ Shave biopsy establishes a definitive histopathologic diagnosis and often is curative. Given that lesions of osteoma cutis themselves are benign, removal may not be necessary.