Dermatopathology

Basal cell carcinoma (BCC) is the most common type of skin cancer frequently encountered in both dermatology and primary care settings.¹ When biopsies of these neoplasms are performed to confirm the diagnosis, pathology reports may indicate positive or negative margin status. No guidelines exist for reporting biopsy margin status for BCC, resulting in varied reporting practices among dermatopathologists. Furthermore, the terminology used to describe margin status can be ambiguous and differs among pathologists; language such as “approaches the margin” or “margins appear free” may be used, with nonuniform interpretation between pathologists and providers, leading to variability in patient management.²

When interpreting a negative margin status on a pathology report, one must question if the BCC extends beyond the margin in unexamined sections of the specimen, which could be the result of an irregular tumor growth pattern or tissue processing. It has been estimated that less than 2% of the peripheral surgical margin is ultimately examined when serial cross-sections are prepared histologically (the bread loaf technique). However, this estimation would depend on several variables, including the number and thickness of sections and the amount of tissue discarded during processing.³ Importantly, reports of a false-negative margin could lead both the clinician and patient to believe that the neoplasm has been completely removed, which could have serious consequences.

Our study sought to determine the reliability of negative biopsy margin status for BCC. We examined BCC biopsy specimens initially determined to have uninvolved margins on routine tissue processing and determined the proportion with truly negative margins after complete tissue block sectioning of the initial biopsy specimen. We felt this technique was a more accurate measurement of true margin status than examination of a re-excision specimen. We also identified any factors that were predictive of positive true margins.

Methods

We conducted a retrospective study evaluating tissue samples collected at Geisinger Health System (Danville, Pennsylvania) from January to December 2016. Specimens were queried via the electronic database system at our institution (CoPath). We included BCC biopsy specimens with negative histologic margins on initial assessment that subsequently had block exhaust levels routinely ordered. These levels are cut every 100 to 150 µm, generating approximately 8 glass slides. We excluded all tumors that did not fit these criteria as well as those in patients younger than 18 years. Data collection was performed utilizing specimen pathology reports in addition to the note from the corresponding clinician office visit from the institution’s electronic medical record (Epic). Appropriate statistical calculations were performed. This study was approved by an institutional review board at our institution, which is required for all research involving human participants. This served to ensure the proper review and storage of patients’ protected health information.

 

Results

The search yielded a total of 122 specimens from 104 patients after appropriate exclusions. We examined a total of 122 BCC biopsy specimens with negative initial margins: 121 (99.2%) shave biopsies and 1 (0.8%) punch biopsy. Of 122 specimens with negative initial margins, 53 (43.4%) were found to have a truly positive margin based on the presence of either tumor or stroma at the lateral or deep tissue edge after complete tissue block sectioning. Sixty-nine (56.6%) specimens had clear margins and were categorized as truly negative after complete tissue block sectioning. Specimens with positive and negative final margin status did not differ significantly with respect to patient age; gender; biopsy technique; number of gross specimen sections; or tumor characteristics, including location, size, and subtype (Table)(P>.05).

We also examined the type of treatment performed, which varied and included curettage, electrodesiccation and curettage, excision, and Mohs micrographic surgery. Clinicians, who were not made aware of the exhaust level protocol, chose not to pursue further treatment in 6 (4.9%) of the cases because of negative biopsy margins. Four (66.7%) of the 6 providers were physicians, and 2 (33.3%) were advanced practitioners. All of the providers practiced within the Department of Dermatology.

Comment

Our findings support prior smaller studies investigating this topic. A prospective study by Schnebelen et al⁴ examined 27 BCC biopsy specimens and found that 8 (30%) were erroneously classified as negative on routine examination. This study similarly determined true margin status by assessing the margins at complete tissue block exhaustion.⁴ Willardson et al⁵ also demonstrated the poor predictive value of margin status based on the presence of residual BCC in subsequent excisions. They found that 34 (24%) of 143 cases with negative biopsy margins contained residual tumor in the corresponding excision.⁵

Our study revealed that almost half of BCC biopsy specimens that had negative histologic margins with routine sectioning had truly positive margins on complete block exhaustion. This finding was independent of multiple factors, including tumor subtype, indicating that even nonaggressive tumors are prone to false-negative margin reports. We also found that reports of negative margins persuaded some clinicians to forgo definitive treatment. This study serves to remind clinicians of the limitations of margin assessment and provides impetus for dermatopathologists to consider modifying how margin status is reported.

Limitations of this study include a small number of cases and limited generalizability. Institutions that routinely examine more levels of each biopsy specimen may be less likely to erroneously categorize a positive margin as negative. Furthermore, despite exhausting the tissue block, we still may have underestimated the number of cases with truly positive margins, as this method inherently does not allow for complete margin examination.

Acknowledgments
We thank the Geisinger Department of Dermatopathology and the Geisinger Biostatistics & Research Data Core (Danville, Pennsylvania) for their assistance with our project.

Basal cell carcinoma (BCC) is the most common type of skin cancer frequently encountered in both dermatology and primary care settings.¹ When biopsies of these neoplasms are performed to confirm the diagnosis, pathology reports may indicate positive or negative margin status. No guidelines exist for reporting biopsy margin status for BCC, resulting in varied reporting practices among dermatopathologists. Furthermore, the terminology used to describe margin status can be ambiguous and differs among pathologists; language such as “approaches the margin” or “margins appear free” may be used, with nonuniform interpretation between pathologists and providers, leading to variability in patient management.²

When interpreting a negative margin status on a pathology report, one must question if the BCC extends beyond the margin in unexamined sections of the specimen, which could be the result of an irregular tumor growth pattern or tissue processing. It has been estimated that less than 2% of the peripheral surgical margin is ultimately examined when serial cross-sections are prepared histologically (the bread loaf technique). However, this estimation would depend on several variables, including the number and thickness of sections and the amount of tissue discarded during processing.³ Importantly, reports of a false-negative margin could lead both the clinician and patient to believe that the neoplasm has been completely removed, which could have serious consequences.

Our study sought to determine the reliability of negative biopsy margin status for BCC. We examined BCC biopsy specimens initially determined to have uninvolved margins on routine tissue processing and determined the proportion with truly negative margins after complete tissue block sectioning of the initial biopsy specimen. We felt this technique was a more accurate measurement of true margin status than examination of a re-excision specimen. We also identified any factors that were predictive of positive true margins.

Methods

We conducted a retrospective study evaluating tissue samples collected at Geisinger Health System (Danville, Pennsylvania) from January to December 2016. Specimens were queried via the electronic database system at our institution (CoPath). We included BCC biopsy specimens with negative histologic margins on initial assessment that subsequently had block exhaust levels routinely ordered. These levels are cut every 100 to 150 µm, generating approximately 8 glass slides. We excluded all tumors that did not fit these criteria as well as those in patients younger than 18 years. Data collection was performed utilizing specimen pathology reports in addition to the note from the corresponding clinician office visit from the institution’s electronic medical record (Epic). Appropriate statistical calculations were performed. This study was approved by an institutional review board at our institution, which is required for all research involving human participants. This served to ensure the proper review and storage of patients’ protected health information.

 

Results

The search yielded a total of 122 specimens from 104 patients after appropriate exclusions. We examined a total of 122 BCC biopsy specimens with negative initial margins: 121 (99.2%) shave biopsies and 1 (0.8%) punch biopsy. Of 122 specimens with negative initial margins, 53 (43.4%) were found to have a truly positive margin based on the presence of either tumor or stroma at the lateral or deep tissue edge after complete tissue block sectioning. Sixty-nine (56.6%) specimens had clear margins and were categorized as truly negative after complete tissue block sectioning. Specimens with positive and negative final margin status did not differ significantly with respect to patient age; gender; biopsy technique; number of gross specimen sections; or tumor characteristics, including location, size, and subtype (Table)(P>.05).

We also examined the type of treatment performed, which varied and included curettage, electrodesiccation and curettage, excision, and Mohs micrographic surgery. Clinicians, who were not made aware of the exhaust level protocol, chose not to pursue further treatment in 6 (4.9%) of the cases because of negative biopsy margins. Four (66.7%) of the 6 providers were physicians, and 2 (33.3%) were advanced practitioners. All of the providers practiced within the Department of Dermatology.

Comment

Our findings support prior smaller studies investigating this topic. A prospective study by Schnebelen et al⁴ examined 27 BCC biopsy specimens and found that 8 (30%) were erroneously classified as negative on routine examination. This study similarly determined true margin status by assessing the margins at complete tissue block exhaustion.⁴ Willardson et al⁵ also demonstrated the poor predictive value of margin status based on the presence of residual BCC in subsequent excisions. They found that 34 (24%) of 143 cases with negative biopsy margins contained residual tumor in the corresponding excision.⁵

Our study revealed that almost half of BCC biopsy specimens that had negative histologic margins with routine sectioning had truly positive margins on complete block exhaustion. This finding was independent of multiple factors, including tumor subtype, indicating that even nonaggressive tumors are prone to false-negative margin reports. We also found that reports of negative margins persuaded some clinicians to forgo definitive treatment. This study serves to remind clinicians of the limitations of margin assessment and provides impetus for dermatopathologists to consider modifying how margin status is reported.

Limitations of this study include a small number of cases and limited generalizability. Institutions that routinely examine more levels of each biopsy specimen may be less likely to erroneously categorize a positive margin as negative. Furthermore, despite exhausting the tissue block, we still may have underestimated the number of cases with truly positive margins, as this method inherently does not allow for complete margin examination.

Acknowledgments
We thank the Geisinger Department of Dermatopathology and the Geisinger Biostatistics & Research Data Core (Danville, Pennsylvania) for their assistance with our project.

Basal cell carcinoma (BCC) is the most common type of skin cancer frequently encountered in both dermatology and primary care settings.¹ When biopsies of these neoplasms are performed to confirm the diagnosis, pathology reports may indicate positive or negative margin status. No guidelines exist for reporting biopsy margin status for BCC, resulting in varied reporting practices among dermatopathologists. Furthermore, the terminology used to describe margin status can be ambiguous and differs among pathologists; language such as “approaches the margin” or “margins appear free” may be used, with nonuniform interpretation between pathologists and providers, leading to variability in patient management.²

When interpreting a negative margin status on a pathology report, one must question if the BCC extends beyond the margin in unexamined sections of the specimen, which could be the result of an irregular tumor growth pattern or tissue processing. It has been estimated that less than 2% of the peripheral surgical margin is ultimately examined when serial cross-sections are prepared histologically (the bread loaf technique). However, this estimation would depend on several variables, including the number and thickness of sections and the amount of tissue discarded during processing.³ Importantly, reports of a false-negative margin could lead both the clinician and patient to believe that the neoplasm has been completely removed, which could have serious consequences.

Our study sought to determine the reliability of negative biopsy margin status for BCC. We examined BCC biopsy specimens initially determined to have uninvolved margins on routine tissue processing and determined the proportion with truly negative margins after complete tissue block sectioning of the initial biopsy specimen. We felt this technique was a more accurate measurement of true margin status than examination of a re-excision specimen. We also identified any factors that were predictive of positive true margins.

Methods

We conducted a retrospective study evaluating tissue samples collected at Geisinger Health System (Danville, Pennsylvania) from January to December 2016. Specimens were queried via the electronic database system at our institution (CoPath). We included BCC biopsy specimens with negative histologic margins on initial assessment that subsequently had block exhaust levels routinely ordered. These levels are cut every 100 to 150 µm, generating approximately 8 glass slides. We excluded all tumors that did not fit these criteria as well as those in patients younger than 18 years. Data collection was performed utilizing specimen pathology reports in addition to the note from the corresponding clinician office visit from the institution’s electronic medical record (Epic). Appropriate statistical calculations were performed. This study was approved by an institutional review board at our institution, which is required for all research involving human participants. This served to ensure the proper review and storage of patients’ protected health information.

 

Results

The search yielded a total of 122 specimens from 104 patients after appropriate exclusions. We examined a total of 122 BCC biopsy specimens with negative initial margins: 121 (99.2%) shave biopsies and 1 (0.8%) punch biopsy. Of 122 specimens with negative initial margins, 53 (43.4%) were found to have a truly positive margin based on the presence of either tumor or stroma at the lateral or deep tissue edge after complete tissue block sectioning. Sixty-nine (56.6%) specimens had clear margins and were categorized as truly negative after complete tissue block sectioning. Specimens with positive and negative final margin status did not differ significantly with respect to patient age; gender; biopsy technique; number of gross specimen sections; or tumor characteristics, including location, size, and subtype (Table)(P>.05).

We also examined the type of treatment performed, which varied and included curettage, electrodesiccation and curettage, excision, and Mohs micrographic surgery. Clinicians, who were not made aware of the exhaust level protocol, chose not to pursue further treatment in 6 (4.9%) of the cases because of negative biopsy margins. Four (66.7%) of the 6 providers were physicians, and 2 (33.3%) were advanced practitioners. All of the providers practiced within the Department of Dermatology.

Comment

Our findings support prior smaller studies investigating this topic. A prospective study by Schnebelen et al⁴ examined 27 BCC biopsy specimens and found that 8 (30%) were erroneously classified as negative on routine examination. This study similarly determined true margin status by assessing the margins at complete tissue block exhaustion.⁴ Willardson et al⁵ also demonstrated the poor predictive value of margin status based on the presence of residual BCC in subsequent excisions. They found that 34 (24%) of 143 cases with negative biopsy margins contained residual tumor in the corresponding excision.⁵

Our study revealed that almost half of BCC biopsy specimens that had negative histologic margins with routine sectioning had truly positive margins on complete block exhaustion. This finding was independent of multiple factors, including tumor subtype, indicating that even nonaggressive tumors are prone to false-negative margin reports. We also found that reports of negative margins persuaded some clinicians to forgo definitive treatment. This study serves to remind clinicians of the limitations of margin assessment and provides impetus for dermatopathologists to consider modifying how margin status is reported.

Limitations of this study include a small number of cases and limited generalizability. Institutions that routinely examine more levels of each biopsy specimen may be less likely to erroneously categorize a positive margin as negative. Furthermore, despite exhausting the tissue block, we still may have underestimated the number of cases with truly positive margins, as this method inherently does not allow for complete margin examination.

Acknowledgments
We thank the Geisinger Department of Dermatopathology and the Geisinger Biostatistics & Research Data Core (Danville, Pennsylvania) for their assistance with our project.

To the Editor:

A 32-year-old man presented to the dermatology clinic with multiple asymptomatic blue lesions on the arms and upper torso of 15 years’ duration. His medical history was notable for a recent diagnosis of malignant melanoma following excision of a mole on the upper back 4 months prior. He reported that the mole had been present since childhood, but his sister noticed that it increased in size and changed in color over the course of a year. Physical examination showed multiple blue subcutaneous nodules on the bilateral arms and lower back. The nodules were soft and nontender, and some had telangiectasia on the overlying skin.

Given the atypical distribution of nodules and the patient’s recent history of melanoma, there was concern for cutaneous metastases. A punch biopsy of one of the nodules on the right upper arm was performed. Microscopic examination of the biopsy specimen revealed a proliferation of multiple cavernous vessels surrounded by several rows of monotonous round cells with moderate eosinophilic cytoplasm and monomorphic nuclei, which was consistent with a diagnosis of glomangioma (Figure 1). Immunohistochemical analysis showed diffuse positive staining for smooth muscle actin (Figure 2); CD34 immunostain was positive in endothelial cells and negative in tumor cells (Figure 3).

Two weeks after the first punch biopsy, the patient returned for follow-up. He noted a new soft, painless, nontender mass in the left axillary region. Positron emission tomography–computed tomography and a lymphoscintigram were performed to assess for lymphadenopathy, but they were not contributory. Subsequently, the patient underwent bilateral axillary sentinel lymph node dissection, which revealed the presence of metastatic melanoma in one lymph node in the left axilla. No metastatic disease was identified in the right axillary sentinel lymph nodes. A second skin biopsy was performed on another blue nodule to confirm the diagnosis and to exclude the possibility of sampling error. The histopathologic examination again revealed glomangioma, which established the diagnosis of multiple glomangiomas.

Glomus tumors arise from modified smooth muscle cells located in glomus bodies. The glomus body is a component of the dermis involved in regulation of body temperature that is composed of an afferent arteriole and an efferent venule. The arterial end of this apparatus, known as the Sucquet-Hoyer canal, is surrounded by glomus cells that have a contractile capability similar to smooth muscle cells. Glomus tumors usually present as painful masses on the fingers with a typical subungual location and almost always are solitary.¹ Glomangiomas, sometimes known as glomuvenous malformations, tend to be larger and usually are painless. They mostly are found on the trunk and extremities and can appear in groups.^2,3 Histopathologically, glomus tumors are circumscribed lesions that show a predominance of glomus cells surrounding inconspicuous blood vessels. Glomangiomas are less well-circumscribed and show a more vascular architecture with prominent dilated vessels and a smaller number of glomus cells.⁴

We present a case of a patient with multiple glomangiomas. There are few reports of multiple glomangiomas in the literature. This case is particularly interesting in that our patient had a history of malignant melanoma, and there was a concern for skin metastases. Despite the patient’s personal history of blue lesions that predated the diagnosis of melanoma for many years, we could not exclude the possibility of cutaneous metastases without performing biopsies.

Tumors of glomus cell origin usually are benign. It has been suggested to replace the term glomangioma with glomuvenous malformations to emphasize the hamartomatous nature of these lesions.⁵ Glomuvenous malformations, or glomangiomas, can occur sporadically or can be inherited as a familial disorder. Inheritable glomangioma has been linked to the chromosome 1p21-22 locus and mutations in the glomulin gene, GLMN, with variable penetrance.⁶ Our patient did not report a family history of such lesions.

Glomangiomas typically are solitary but rarely can present as multiple lesions in fewer than 10% of cases.⁷ Multiple glomangiomas are classified into 3 subtypes: localized, disseminated, and congenital plaque type. Localized multiple glomangiomas present as blue nodules confined to 1 anatomic location such as the hand or arm. Disseminated glomangiomas are more widely distributed and involve more than 1 anatomic location.⁸ Plaque-type glomangiomas consist of numerous confluent lesions occurring either as solitary or multiple plaques.² Clinically, glomangiomas manifest as painless to mildly painful cutaneous nodules. Compared to venous malformations, glomangiomas are less compressible under external pressure.

Histopathologically, glomangiomas appear as nonencapsulated tumors with large, irregular, prominent vessels lined by glomus cells. Glomus cells may be so sparse that the distinction from venous malformations and hemangiomas becomes difficult. Immunohistochemistry can play an important role in diagnosis. As modified smooth muscle cells, glomus cells stain positive with a-smooth muscle actin, while CD34 highlights the vascular endothelium.¹The clinical differential diagnosis of multiple blue or violaceous subcutaneous nodules includes blue rubber bleb nevus syndrome, Maffucci syndrome, glomus tumor, pyogenic granuloma, hemangioma, spiradenoma, angiolipoma, leiomyoma, or hemangiopericytoma.^9-12

Different treatment modalities are available for solitary glomangiomas, including surgical excision, sclerotherapy, and laser application. Treatment of multiple glomangiomas may not be feasible, and excision of isolated symptomatic lesions may be the only option; however, it is crucial to reach the correct diagnosis in these patients to avoid improper treatments and interventions.

To the Editor:

A 32-year-old man presented to the dermatology clinic with multiple asymptomatic blue lesions on the arms and upper torso of 15 years’ duration. His medical history was notable for a recent diagnosis of malignant melanoma following excision of a mole on the upper back 4 months prior. He reported that the mole had been present since childhood, but his sister noticed that it increased in size and changed in color over the course of a year. Physical examination showed multiple blue subcutaneous nodules on the bilateral arms and lower back. The nodules were soft and nontender, and some had telangiectasia on the overlying skin.

Given the atypical distribution of nodules and the patient’s recent history of melanoma, there was concern for cutaneous metastases. A punch biopsy of one of the nodules on the right upper arm was performed. Microscopic examination of the biopsy specimen revealed a proliferation of multiple cavernous vessels surrounded by several rows of monotonous round cells with moderate eosinophilic cytoplasm and monomorphic nuclei, which was consistent with a diagnosis of glomangioma (Figure 1). Immunohistochemical analysis showed diffuse positive staining for smooth muscle actin (Figure 2); CD34 immunostain was positive in endothelial cells and negative in tumor cells (Figure 3).

Two weeks after the first punch biopsy, the patient returned for follow-up. He noted a new soft, painless, nontender mass in the left axillary region. Positron emission tomography–computed tomography and a lymphoscintigram were performed to assess for lymphadenopathy, but they were not contributory. Subsequently, the patient underwent bilateral axillary sentinel lymph node dissection, which revealed the presence of metastatic melanoma in one lymph node in the left axilla. No metastatic disease was identified in the right axillary sentinel lymph nodes. A second skin biopsy was performed on another blue nodule to confirm the diagnosis and to exclude the possibility of sampling error. The histopathologic examination again revealed glomangioma, which established the diagnosis of multiple glomangiomas.

Glomus tumors arise from modified smooth muscle cells located in glomus bodies. The glomus body is a component of the dermis involved in regulation of body temperature that is composed of an afferent arteriole and an efferent venule. The arterial end of this apparatus, known as the Sucquet-Hoyer canal, is surrounded by glomus cells that have a contractile capability similar to smooth muscle cells. Glomus tumors usually present as painful masses on the fingers with a typical subungual location and almost always are solitary.¹ Glomangiomas, sometimes known as glomuvenous malformations, tend to be larger and usually are painless. They mostly are found on the trunk and extremities and can appear in groups.^2,3 Histopathologically, glomus tumors are circumscribed lesions that show a predominance of glomus cells surrounding inconspicuous blood vessels. Glomangiomas are less well-circumscribed and show a more vascular architecture with prominent dilated vessels and a smaller number of glomus cells.⁴

We present a case of a patient with multiple glomangiomas. There are few reports of multiple glomangiomas in the literature. This case is particularly interesting in that our patient had a history of malignant melanoma, and there was a concern for skin metastases. Despite the patient’s personal history of blue lesions that predated the diagnosis of melanoma for many years, we could not exclude the possibility of cutaneous metastases without performing biopsies.

Tumors of glomus cell origin usually are benign. It has been suggested to replace the term glomangioma with glomuvenous malformations to emphasize the hamartomatous nature of these lesions.⁵ Glomuvenous malformations, or glomangiomas, can occur sporadically or can be inherited as a familial disorder. Inheritable glomangioma has been linked to the chromosome 1p21-22 locus and mutations in the glomulin gene, GLMN, with variable penetrance.⁶ Our patient did not report a family history of such lesions.

Glomangiomas typically are solitary but rarely can present as multiple lesions in fewer than 10% of cases.⁷ Multiple glomangiomas are classified into 3 subtypes: localized, disseminated, and congenital plaque type. Localized multiple glomangiomas present as blue nodules confined to 1 anatomic location such as the hand or arm. Disseminated glomangiomas are more widely distributed and involve more than 1 anatomic location.⁸ Plaque-type glomangiomas consist of numerous confluent lesions occurring either as solitary or multiple plaques.² Clinically, glomangiomas manifest as painless to mildly painful cutaneous nodules. Compared to venous malformations, glomangiomas are less compressible under external pressure.

Histopathologically, glomangiomas appear as nonencapsulated tumors with large, irregular, prominent vessels lined by glomus cells. Glomus cells may be so sparse that the distinction from venous malformations and hemangiomas becomes difficult. Immunohistochemistry can play an important role in diagnosis. As modified smooth muscle cells, glomus cells stain positive with a-smooth muscle actin, while CD34 highlights the vascular endothelium.¹The clinical differential diagnosis of multiple blue or violaceous subcutaneous nodules includes blue rubber bleb nevus syndrome, Maffucci syndrome, glomus tumor, pyogenic granuloma, hemangioma, spiradenoma, angiolipoma, leiomyoma, or hemangiopericytoma.^9-12

Different treatment modalities are available for solitary glomangiomas, including surgical excision, sclerotherapy, and laser application. Treatment of multiple glomangiomas may not be feasible, and excision of isolated symptomatic lesions may be the only option; however, it is crucial to reach the correct diagnosis in these patients to avoid improper treatments and interventions.

To the Editor:

A 32-year-old man presented to the dermatology clinic with multiple asymptomatic blue lesions on the arms and upper torso of 15 years’ duration. His medical history was notable for a recent diagnosis of malignant melanoma following excision of a mole on the upper back 4 months prior. He reported that the mole had been present since childhood, but his sister noticed that it increased in size and changed in color over the course of a year. Physical examination showed multiple blue subcutaneous nodules on the bilateral arms and lower back. The nodules were soft and nontender, and some had telangiectasia on the overlying skin.

Given the atypical distribution of nodules and the patient’s recent history of melanoma, there was concern for cutaneous metastases. A punch biopsy of one of the nodules on the right upper arm was performed. Microscopic examination of the biopsy specimen revealed a proliferation of multiple cavernous vessels surrounded by several rows of monotonous round cells with moderate eosinophilic cytoplasm and monomorphic nuclei, which was consistent with a diagnosis of glomangioma (Figure 1). Immunohistochemical analysis showed diffuse positive staining for smooth muscle actin (Figure 2); CD34 immunostain was positive in endothelial cells and negative in tumor cells (Figure 3).

Two weeks after the first punch biopsy, the patient returned for follow-up. He noted a new soft, painless, nontender mass in the left axillary region. Positron emission tomography–computed tomography and a lymphoscintigram were performed to assess for lymphadenopathy, but they were not contributory. Subsequently, the patient underwent bilateral axillary sentinel lymph node dissection, which revealed the presence of metastatic melanoma in one lymph node in the left axilla. No metastatic disease was identified in the right axillary sentinel lymph nodes. A second skin biopsy was performed on another blue nodule to confirm the diagnosis and to exclude the possibility of sampling error. The histopathologic examination again revealed glomangioma, which established the diagnosis of multiple glomangiomas.

Glomus tumors arise from modified smooth muscle cells located in glomus bodies. The glomus body is a component of the dermis involved in regulation of body temperature that is composed of an afferent arteriole and an efferent venule. The arterial end of this apparatus, known as the Sucquet-Hoyer canal, is surrounded by glomus cells that have a contractile capability similar to smooth muscle cells. Glomus tumors usually present as painful masses on the fingers with a typical subungual location and almost always are solitary.¹ Glomangiomas, sometimes known as glomuvenous malformations, tend to be larger and usually are painless. They mostly are found on the trunk and extremities and can appear in groups.^2,3 Histopathologically, glomus tumors are circumscribed lesions that show a predominance of glomus cells surrounding inconspicuous blood vessels. Glomangiomas are less well-circumscribed and show a more vascular architecture with prominent dilated vessels and a smaller number of glomus cells.⁴

We present a case of a patient with multiple glomangiomas. There are few reports of multiple glomangiomas in the literature. This case is particularly interesting in that our patient had a history of malignant melanoma, and there was a concern for skin metastases. Despite the patient’s personal history of blue lesions that predated the diagnosis of melanoma for many years, we could not exclude the possibility of cutaneous metastases without performing biopsies.

Tumors of glomus cell origin usually are benign. It has been suggested to replace the term glomangioma with glomuvenous malformations to emphasize the hamartomatous nature of these lesions.⁵ Glomuvenous malformations, or glomangiomas, can occur sporadically or can be inherited as a familial disorder. Inheritable glomangioma has been linked to the chromosome 1p21-22 locus and mutations in the glomulin gene, GLMN, with variable penetrance.⁶ Our patient did not report a family history of such lesions.

Glomangiomas typically are solitary but rarely can present as multiple lesions in fewer than 10% of cases.⁷ Multiple glomangiomas are classified into 3 subtypes: localized, disseminated, and congenital plaque type. Localized multiple glomangiomas present as blue nodules confined to 1 anatomic location such as the hand or arm. Disseminated glomangiomas are more widely distributed and involve more than 1 anatomic location.⁸ Plaque-type glomangiomas consist of numerous confluent lesions occurring either as solitary or multiple plaques.² Clinically, glomangiomas manifest as painless to mildly painful cutaneous nodules. Compared to venous malformations, glomangiomas are less compressible under external pressure.

Histopathologically, glomangiomas appear as nonencapsulated tumors with large, irregular, prominent vessels lined by glomus cells. Glomus cells may be so sparse that the distinction from venous malformations and hemangiomas becomes difficult. Immunohistochemistry can play an important role in diagnosis. As modified smooth muscle cells, glomus cells stain positive with a-smooth muscle actin, while CD34 highlights the vascular endothelium.¹The clinical differential diagnosis of multiple blue or violaceous subcutaneous nodules includes blue rubber bleb nevus syndrome, Maffucci syndrome, glomus tumor, pyogenic granuloma, hemangioma, spiradenoma, angiolipoma, leiomyoma, or hemangiopericytoma.^9-12

Different treatment modalities are available for solitary glomangiomas, including surgical excision, sclerotherapy, and laser application. Treatment of multiple glomangiomas may not be feasible, and excision of isolated symptomatic lesions may be the only option; however, it is crucial to reach the correct diagnosis in these patients to avoid improper treatments and interventions.

The Diagnosis: Piloleiomyoma 

Leiomyoma cutis, also known as cutaneous leiomyoma, is a benign smooth muscle tumor first described in 1854.¹ Cutaneous leiomyoma is comprised of 3 distinct types that depend on the origin of smooth muscle tumor: piloleiomyoma (arrector pili muscle), angioleiomyoma (tunica media of arteries/veins), and genital leiomyoma (dartos muscle of the scrotum and labia majora, erectile muscle of nipple).² It affects both sexes equally, though some reports have noted an increased prevalence in females. Piloleiomyomas commonly present on the extensor surfaces of the extremities (solitary) and trunk (multiple).¹ Tumors most often present as firm flesh-colored or pink-brown papulonodules. They can be linear, dermatomal, segmental, or diffuse, and often are painful. Clinical differential diagnosis for painful skin tumors is aided by the acronym "BLEND AN EGG": blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor.³ For isolated lesions, surgical excision is the treatment of choice. For numerous lesions in which excision would not be feasible, intralesional corticosteroids, medications (eg, calcium channel blockers, alpha blockers, nitroglycerin), and botulinum toxin have been used for pain relief.⁴  

Notably, multiple cutaneous leiomyomas can be seen in association with uterine leiomyomas in Reed syndrome due to an autosomal-dominant or de novo mutation in the fumarate hydratase gene, FH. Reed syndrome is associated with a lifetime risk for renal cell carcinoma (hereditary leiomyomatosis and renal cell cancer) in 15% of cases with FH mutations.⁵ In our patient, both immunohistochemical staining and blood testing for FH were performed. Immunohistochemistry revealed notably diminished staining with only weak patchy granular cytoplasmic staining present (Figure 1). Genetic testing revealed heterozygosity for a pathogenic variant of the FH gene, consistent with a diagnosis of Reed syndrome.  

Histologically, the differential diagnosis includes other spindle cell tumors, such as dermatofibroma, neurofibroma, and dermatomyofibroma. The histologic appearance varies depending on the type, with piloleiomyoma typically located within the reticular dermis with possible subcutaneous extension. Fascicles of eosinophilic smooth muscle cells in an interlacing arrangement often ramify between neighboring dermal collagen; these smooth muscle cells contain cigar-shaped, blunt-ended nuclei with a perinuclear clear vacuole. Marked epidermal hyperplasia is possible.⁶ A close association with a nearby hair follicle frequently is noted. Although differentiated smooth muscle cells usually are evident on hematoxylin and eosin, positive staining for smooth muscle actin (SMA) and desmin can aid in diagnosis.⁷ Immunohistochemical staining for FH has proven to be highly specific (97.6%) with moderate sensitivity (70.0%).⁸ Angioleiomyomas appear as well-demarcated dermal to subcutaneous tumors composed of smooth muscle cells surrounding thick-walled vaculature.⁹ Scrotal and vulvar leiomyomas are composed of eosinophilic spindle cells, though vulvar leiomyomas have shown epithelioid differentiation.¹⁰ Nipple leiomyomas appear similar to piloleiomyomas on histology with interlacing smooth muscle fiber bundles.  

Eccrine spiradenoma is a relatively uncommon adnexal tumor derived from eccrine sweat glands. It most often presents as a small, painful or tender, intradermal nodule (or rarely as nodules) on the head or ventral trunk.¹¹ There is no sexual predilection. It affects adults at any age but most often from 15 to 35 years. Although rare, malignant transformation is possible. Histologically, eccrine spiradenomas appear as a well-demarcated dermal tumor composed of bland basaloid cells with minimal cytoplasm, often with numerous admixed lymphocytes and variably prominent vasculature (Figure 2). Eosinophilic basement membrane material can be seen within or surrounding the nodules of tumor cells. Multiple spiradenomas can occur in the setting of Brooke-Spiegler syndrome, which is an autosomal-dominant disorder due to an inherited mutation in the CYLD gene. Spiradenomas are benign neoplasms, and surgical excision with clear margins is the treatment of choice.¹²  

Dermatofibroma, also known as cutaneous benign fibrous histiocytoma, is a firm, flesh-colored papule or nodule that most often presents on the lower extremities. It typically is seen in women aged 20 to 40 years.¹³ The etiology is uncertain, and dermatofibromas often spontaneously develop, though there are inconsistent reports of development with local trauma including insect bites and puncture wounds. The dimple sign refers to skin dimpling with lateral pressure.¹³ Most commonly, dermatofibromas consist of a dermal proliferation of bland fibroblastic cells with entrapment of dermal collagen bundles at the periphery of the tumors (Figure 3). The fibroblastic cells often are paler and less eosinophilic than smooth muscle cells seen in cutaneous leiomyomas, with tapered nuclei that lack a perinuclear vacuole. Admixed histocytes and other inflammatory cells often are present. Overlying epidermal hyperplasia and/or hyperpigmentation also may be present. Numerous histologic variants have been described, including cellular, epithelioid, aneurysmal, atypical, and hemosiderotic types.¹⁴ Immunohistochemical stains may show patchy positive staining for SMA, but h-caldesmon and desmin typically are negative.  

Neurofibroma is a tumor derived from neuromesenchymal tissue with nerve axons. They form through neuromesenchyme (eg, Schwann cells, mast cells, perineural cells, endoneural fibroblast) proliferation. Solitary neurofibromas occur most commonly in adults and have no gender predilection. The most common presentation is an asymptomatic, solitary, soft, flesh-colored papulonodule.¹⁵ Clinical variants include pigmented, diffuse, and plexiform, with plexiform neurofibromas almost always being consistent with a diagnosis of neurofibromatosis type 1. Histologically, neurofibromas present as dermal or subcutaneous nodules composed of randomly arranged spindle cells with wavy tapered nuclei within a loose collagenous stroma (Figure 4).¹⁶ The spindle cells in neurofibromas will stain positively for S-100 protein and SOX-10 and negatively for SMA and desmin.  

Angiolipoma is a benign tumor composed of adipocytes that also contains vasculature.¹⁷ The majority of cases are of unknown etiology, though familial cases have been described. They typically present as multiple painful or tender (differentiating from lipomas) subcutaneous swellings over the forearms in individuals aged 20 to 30 years.¹⁸ On histopathology, angiolipomas appear as well-circumscribed subcutaneous tumors containing mature adipocytes intermixed with small capillary vessels, some of which contain luminal fibrin thrombi (Figure 5).  

The Diagnosis: Piloleiomyoma 

Leiomyoma cutis, also known as cutaneous leiomyoma, is a benign smooth muscle tumor first described in 1854.¹ Cutaneous leiomyoma is comprised of 3 distinct types that depend on the origin of smooth muscle tumor: piloleiomyoma (arrector pili muscle), angioleiomyoma (tunica media of arteries/veins), and genital leiomyoma (dartos muscle of the scrotum and labia majora, erectile muscle of nipple).² It affects both sexes equally, though some reports have noted an increased prevalence in females. Piloleiomyomas commonly present on the extensor surfaces of the extremities (solitary) and trunk (multiple).¹ Tumors most often present as firm flesh-colored or pink-brown papulonodules. They can be linear, dermatomal, segmental, or diffuse, and often are painful. Clinical differential diagnosis for painful skin tumors is aided by the acronym "BLEND AN EGG": blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor.³ For isolated lesions, surgical excision is the treatment of choice. For numerous lesions in which excision would not be feasible, intralesional corticosteroids, medications (eg, calcium channel blockers, alpha blockers, nitroglycerin), and botulinum toxin have been used for pain relief.⁴  

Notably, multiple cutaneous leiomyomas can be seen in association with uterine leiomyomas in Reed syndrome due to an autosomal-dominant or de novo mutation in the fumarate hydratase gene, FH. Reed syndrome is associated with a lifetime risk for renal cell carcinoma (hereditary leiomyomatosis and renal cell cancer) in 15% of cases with FH mutations.⁵ In our patient, both immunohistochemical staining and blood testing for FH were performed. Immunohistochemistry revealed notably diminished staining with only weak patchy granular cytoplasmic staining present (Figure 1). Genetic testing revealed heterozygosity for a pathogenic variant of the FH gene, consistent with a diagnosis of Reed syndrome.  

Histologically, the differential diagnosis includes other spindle cell tumors, such as dermatofibroma, neurofibroma, and dermatomyofibroma. The histologic appearance varies depending on the type, with piloleiomyoma typically located within the reticular dermis with possible subcutaneous extension. Fascicles of eosinophilic smooth muscle cells in an interlacing arrangement often ramify between neighboring dermal collagen; these smooth muscle cells contain cigar-shaped, blunt-ended nuclei with a perinuclear clear vacuole. Marked epidermal hyperplasia is possible.⁶ A close association with a nearby hair follicle frequently is noted. Although differentiated smooth muscle cells usually are evident on hematoxylin and eosin, positive staining for smooth muscle actin (SMA) and desmin can aid in diagnosis.⁷ Immunohistochemical staining for FH has proven to be highly specific (97.6%) with moderate sensitivity (70.0%).⁸ Angioleiomyomas appear as well-demarcated dermal to subcutaneous tumors composed of smooth muscle cells surrounding thick-walled vaculature.⁹ Scrotal and vulvar leiomyomas are composed of eosinophilic spindle cells, though vulvar leiomyomas have shown epithelioid differentiation.¹⁰ Nipple leiomyomas appear similar to piloleiomyomas on histology with interlacing smooth muscle fiber bundles.  

Eccrine spiradenoma is a relatively uncommon adnexal tumor derived from eccrine sweat glands. It most often presents as a small, painful or tender, intradermal nodule (or rarely as nodules) on the head or ventral trunk.¹¹ There is no sexual predilection. It affects adults at any age but most often from 15 to 35 years. Although rare, malignant transformation is possible. Histologically, eccrine spiradenomas appear as a well-demarcated dermal tumor composed of bland basaloid cells with minimal cytoplasm, often with numerous admixed lymphocytes and variably prominent vasculature (Figure 2). Eosinophilic basement membrane material can be seen within or surrounding the nodules of tumor cells. Multiple spiradenomas can occur in the setting of Brooke-Spiegler syndrome, which is an autosomal-dominant disorder due to an inherited mutation in the CYLD gene. Spiradenomas are benign neoplasms, and surgical excision with clear margins is the treatment of choice.¹²  

Dermatofibroma, also known as cutaneous benign fibrous histiocytoma, is a firm, flesh-colored papule or nodule that most often presents on the lower extremities. It typically is seen in women aged 20 to 40 years.¹³ The etiology is uncertain, and dermatofibromas often spontaneously develop, though there are inconsistent reports of development with local trauma including insect bites and puncture wounds. The dimple sign refers to skin dimpling with lateral pressure.¹³ Most commonly, dermatofibromas consist of a dermal proliferation of bland fibroblastic cells with entrapment of dermal collagen bundles at the periphery of the tumors (Figure 3). The fibroblastic cells often are paler and less eosinophilic than smooth muscle cells seen in cutaneous leiomyomas, with tapered nuclei that lack a perinuclear vacuole. Admixed histocytes and other inflammatory cells often are present. Overlying epidermal hyperplasia and/or hyperpigmentation also may be present. Numerous histologic variants have been described, including cellular, epithelioid, aneurysmal, atypical, and hemosiderotic types.¹⁴ Immunohistochemical stains may show patchy positive staining for SMA, but h-caldesmon and desmin typically are negative.  

Neurofibroma is a tumor derived from neuromesenchymal tissue with nerve axons. They form through neuromesenchyme (eg, Schwann cells, mast cells, perineural cells, endoneural fibroblast) proliferation. Solitary neurofibromas occur most commonly in adults and have no gender predilection. The most common presentation is an asymptomatic, solitary, soft, flesh-colored papulonodule.¹⁵ Clinical variants include pigmented, diffuse, and plexiform, with plexiform neurofibromas almost always being consistent with a diagnosis of neurofibromatosis type 1. Histologically, neurofibromas present as dermal or subcutaneous nodules composed of randomly arranged spindle cells with wavy tapered nuclei within a loose collagenous stroma (Figure 4).¹⁶ The spindle cells in neurofibromas will stain positively for S-100 protein and SOX-10 and negatively for SMA and desmin.  

Angiolipoma is a benign tumor composed of adipocytes that also contains vasculature.¹⁷ The majority of cases are of unknown etiology, though familial cases have been described. They typically present as multiple painful or tender (differentiating from lipomas) subcutaneous swellings over the forearms in individuals aged 20 to 30 years.¹⁸ On histopathology, angiolipomas appear as well-circumscribed subcutaneous tumors containing mature adipocytes intermixed with small capillary vessels, some of which contain luminal fibrin thrombi (Figure 5).  

The Diagnosis: Piloleiomyoma 

Leiomyoma cutis, also known as cutaneous leiomyoma, is a benign smooth muscle tumor first described in 1854.¹ Cutaneous leiomyoma is comprised of 3 distinct types that depend on the origin of smooth muscle tumor: piloleiomyoma (arrector pili muscle), angioleiomyoma (tunica media of arteries/veins), and genital leiomyoma (dartos muscle of the scrotum and labia majora, erectile muscle of nipple).² It affects both sexes equally, though some reports have noted an increased prevalence in females. Piloleiomyomas commonly present on the extensor surfaces of the extremities (solitary) and trunk (multiple).¹ Tumors most often present as firm flesh-colored or pink-brown papulonodules. They can be linear, dermatomal, segmental, or diffuse, and often are painful. Clinical differential diagnosis for painful skin tumors is aided by the acronym "BLEND AN EGG": blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor.³ For isolated lesions, surgical excision is the treatment of choice. For numerous lesions in which excision would not be feasible, intralesional corticosteroids, medications (eg, calcium channel blockers, alpha blockers, nitroglycerin), and botulinum toxin have been used for pain relief.⁴  

Notably, multiple cutaneous leiomyomas can be seen in association with uterine leiomyomas in Reed syndrome due to an autosomal-dominant or de novo mutation in the fumarate hydratase gene, FH. Reed syndrome is associated with a lifetime risk for renal cell carcinoma (hereditary leiomyomatosis and renal cell cancer) in 15% of cases with FH mutations.⁵ In our patient, both immunohistochemical staining and blood testing for FH were performed. Immunohistochemistry revealed notably diminished staining with only weak patchy granular cytoplasmic staining present (Figure 1). Genetic testing revealed heterozygosity for a pathogenic variant of the FH gene, consistent with a diagnosis of Reed syndrome.  

Histologically, the differential diagnosis includes other spindle cell tumors, such as dermatofibroma, neurofibroma, and dermatomyofibroma. The histologic appearance varies depending on the type, with piloleiomyoma typically located within the reticular dermis with possible subcutaneous extension. Fascicles of eosinophilic smooth muscle cells in an interlacing arrangement often ramify between neighboring dermal collagen; these smooth muscle cells contain cigar-shaped, blunt-ended nuclei with a perinuclear clear vacuole. Marked epidermal hyperplasia is possible.⁶ A close association with a nearby hair follicle frequently is noted. Although differentiated smooth muscle cells usually are evident on hematoxylin and eosin, positive staining for smooth muscle actin (SMA) and desmin can aid in diagnosis.⁷ Immunohistochemical staining for FH has proven to be highly specific (97.6%) with moderate sensitivity (70.0%).⁸ Angioleiomyomas appear as well-demarcated dermal to subcutaneous tumors composed of smooth muscle cells surrounding thick-walled vaculature.⁹ Scrotal and vulvar leiomyomas are composed of eosinophilic spindle cells, though vulvar leiomyomas have shown epithelioid differentiation.¹⁰ Nipple leiomyomas appear similar to piloleiomyomas on histology with interlacing smooth muscle fiber bundles.  

Eccrine spiradenoma is a relatively uncommon adnexal tumor derived from eccrine sweat glands. It most often presents as a small, painful or tender, intradermal nodule (or rarely as nodules) on the head or ventral trunk.¹¹ There is no sexual predilection. It affects adults at any age but most often from 15 to 35 years. Although rare, malignant transformation is possible. Histologically, eccrine spiradenomas appear as a well-demarcated dermal tumor composed of bland basaloid cells with minimal cytoplasm, often with numerous admixed lymphocytes and variably prominent vasculature (Figure 2). Eosinophilic basement membrane material can be seen within or surrounding the nodules of tumor cells. Multiple spiradenomas can occur in the setting of Brooke-Spiegler syndrome, which is an autosomal-dominant disorder due to an inherited mutation in the CYLD gene. Spiradenomas are benign neoplasms, and surgical excision with clear margins is the treatment of choice.¹²  

Dermatofibroma, also known as cutaneous benign fibrous histiocytoma, is a firm, flesh-colored papule or nodule that most often presents on the lower extremities. It typically is seen in women aged 20 to 40 years.¹³ The etiology is uncertain, and dermatofibromas often spontaneously develop, though there are inconsistent reports of development with local trauma including insect bites and puncture wounds. The dimple sign refers to skin dimpling with lateral pressure.¹³ Most commonly, dermatofibromas consist of a dermal proliferation of bland fibroblastic cells with entrapment of dermal collagen bundles at the periphery of the tumors (Figure 3). The fibroblastic cells often are paler and less eosinophilic than smooth muscle cells seen in cutaneous leiomyomas, with tapered nuclei that lack a perinuclear vacuole. Admixed histocytes and other inflammatory cells often are present. Overlying epidermal hyperplasia and/or hyperpigmentation also may be present. Numerous histologic variants have been described, including cellular, epithelioid, aneurysmal, atypical, and hemosiderotic types.¹⁴ Immunohistochemical stains may show patchy positive staining for SMA, but h-caldesmon and desmin typically are negative.  

Neurofibroma is a tumor derived from neuromesenchymal tissue with nerve axons. They form through neuromesenchyme (eg, Schwann cells, mast cells, perineural cells, endoneural fibroblast) proliferation. Solitary neurofibromas occur most commonly in adults and have no gender predilection. The most common presentation is an asymptomatic, solitary, soft, flesh-colored papulonodule.¹⁵ Clinical variants include pigmented, diffuse, and plexiform, with plexiform neurofibromas almost always being consistent with a diagnosis of neurofibromatosis type 1. Histologically, neurofibromas present as dermal or subcutaneous nodules composed of randomly arranged spindle cells with wavy tapered nuclei within a loose collagenous stroma (Figure 4).¹⁶ The spindle cells in neurofibromas will stain positively for S-100 protein and SOX-10 and negatively for SMA and desmin.  

Angiolipoma is a benign tumor composed of adipocytes that also contains vasculature.¹⁷ The majority of cases are of unknown etiology, though familial cases have been described. They typically present as multiple painful or tender (differentiating from lipomas) subcutaneous swellings over the forearms in individuals aged 20 to 30 years.¹⁸ On histopathology, angiolipomas appear as well-circumscribed subcutaneous tumors containing mature adipocytes intermixed with small capillary vessels, some of which contain luminal fibrin thrombi (Figure 5).  

 

To the Editor:

Lichen sclerosus is a chronic inflammatory skin disease of unknown cause that predominantly affects the anogenital region, but isolated extragenital lesions occur in 6% to 15% of patients. The buttocks, thighs, neck, shoulder, upper torso, and wrists most commonly are involved; the face rarely is affected.^1,2 Although the etiology of lichen sclerosus remains undetermined, there is growing evidence that autoimmunity may play a role.¹ Lichen sclerosus more commonly is seen in women, and the disease can present at any age, with a bimodal onset in prepubertal children and in postmenopausal women and men in the fourth decade of life.^1-3 A PubMed search of articles indexed for MEDLINE using the terms lichen and eyelid and manually screened revealed 6 cases of lichen sclerosus involving the eyelid.^2-4 We describe a case of lichen sclerosus involving the eyelid and its histopathology.

A 45-year-old woman was referred to dermatology for evaluation of a right lower eyelid lesion of 3 months’ duration. She first noted a small white patch under the eyelid that had doubled in size and felt firm without bleeding or ulceration. Her medical history was unremarkable, and there was no history of ophthalmic conditions, autoimmune disease, trauma, or cancer. An ophthalmic examination was normal, except for a 20×8-mm, flat, depigmented, firm papule with scalloped borders involving the right lower eyelid margin and extending inferiorly without evidence of madarosis or ulceration (Figure 1). She underwent an incisional biopsy that revealed the diagnosis of lichen sclerosus et atrophicus (Figure 2). A full dermatologic evaluation included a genital examination and did not reveal any additional lesions. Tacrolimus ointment was started to avoid the need for long-term use of periocular steroids and their complications.

Extragenital lichen sclerosus typically is asymptomatic and only rarely presents with pruritus, in contrast to genital lichen sclerosus, which characteristically involves pruritus and dyspareunia. Although eyelid involvement is rare, ophthalmic manifestations of lichen sclerosus have included lid notching, ectropion, acquired Brown syndrome, and associated keratoconjunctivitis sicca.^3-5 It characteristically appears as a well-demarcated hypopigmented papule. The differential diagnosis for a hypopigmented papule also includes amelanotic melanoma, basal cell carcinoma, vitiligo, tinea versicolor, lichen simplex chronicus, lichen planus, morphea (localized scleroderma), and systemic scleroderma with eyelid involvement.^1,5

Differentiating lichen sclerosus from these conditions is of importance, as some of them can have notable morbidity and/or mortality. Of all the autoimmune connective tissue disorders, systemic sclerosus has the highest disease-specific mortality.⁶ Morphea, on the other hand, can have considerable morbidity. Morphea involving the head and neck notably increases the risk for neurologic complications such as seizures or central nervous system vasculitis as well as ocular complications such as anterior uveitis.⁶ Of note, genital lichen sclerosus carries an increased risk for squamous cell carcinoma and verrucous carcinoma; however, there have been no reported cases of malignant transformation with extragenital lesions.²

Histopathology is useful to distinguish among these entities. Although there are no specific features separating lichen sclerosus from a morphea overlap and both entities often are classified by clinical presentation, lichen sclerosus demonstrates epidermal atrophy, follicular plugging, homogenized collagen in the upper dermis with dermal edema, and lichenoid lymphocytic infiltrate (Figure 2).¹ Extragenital lesions in particular also have been noted to have more epidermal atrophy and decreased rete ridges.²

First-line treatment of lichen sclerosus includes topical corticosteroids with emollients for supportive therapy. A topical calcineurin inhibitor such as tacrolimus should be considered for patients who do not respond to corticosteroid therapy or in cases in which corticosteroid therapy is contraindicated to avoid steroid-induced glaucoma or undesirable skin atrophy and hypopigmentation.² A collaborative approach including dermatology and internal medicine can help identify a systemic or multisystem process.

 

To the Editor:

Lichen sclerosus is a chronic inflammatory skin disease of unknown cause that predominantly affects the anogenital region, but isolated extragenital lesions occur in 6% to 15% of patients. The buttocks, thighs, neck, shoulder, upper torso, and wrists most commonly are involved; the face rarely is affected.^1,2 Although the etiology of lichen sclerosus remains undetermined, there is growing evidence that autoimmunity may play a role.¹ Lichen sclerosus more commonly is seen in women, and the disease can present at any age, with a bimodal onset in prepubertal children and in postmenopausal women and men in the fourth decade of life.^1-3 A PubMed search of articles indexed for MEDLINE using the terms lichen and eyelid and manually screened revealed 6 cases of lichen sclerosus involving the eyelid.^2-4 We describe a case of lichen sclerosus involving the eyelid and its histopathology.

A 45-year-old woman was referred to dermatology for evaluation of a right lower eyelid lesion of 3 months’ duration. She first noted a small white patch under the eyelid that had doubled in size and felt firm without bleeding or ulceration. Her medical history was unremarkable, and there was no history of ophthalmic conditions, autoimmune disease, trauma, or cancer. An ophthalmic examination was normal, except for a 20×8-mm, flat, depigmented, firm papule with scalloped borders involving the right lower eyelid margin and extending inferiorly without evidence of madarosis or ulceration (Figure 1). She underwent an incisional biopsy that revealed the diagnosis of lichen sclerosus et atrophicus (Figure 2). A full dermatologic evaluation included a genital examination and did not reveal any additional lesions. Tacrolimus ointment was started to avoid the need for long-term use of periocular steroids and their complications.

Extragenital lichen sclerosus typically is asymptomatic and only rarely presents with pruritus, in contrast to genital lichen sclerosus, which characteristically involves pruritus and dyspareunia. Although eyelid involvement is rare, ophthalmic manifestations of lichen sclerosus have included lid notching, ectropion, acquired Brown syndrome, and associated keratoconjunctivitis sicca.^3-5 It characteristically appears as a well-demarcated hypopigmented papule. The differential diagnosis for a hypopigmented papule also includes amelanotic melanoma, basal cell carcinoma, vitiligo, tinea versicolor, lichen simplex chronicus, lichen planus, morphea (localized scleroderma), and systemic scleroderma with eyelid involvement.^1,5

Differentiating lichen sclerosus from these conditions is of importance, as some of them can have notable morbidity and/or mortality. Of all the autoimmune connective tissue disorders, systemic sclerosus has the highest disease-specific mortality.⁶ Morphea, on the other hand, can have considerable morbidity. Morphea involving the head and neck notably increases the risk for neurologic complications such as seizures or central nervous system vasculitis as well as ocular complications such as anterior uveitis.⁶ Of note, genital lichen sclerosus carries an increased risk for squamous cell carcinoma and verrucous carcinoma; however, there have been no reported cases of malignant transformation with extragenital lesions.²

Histopathology is useful to distinguish among these entities. Although there are no specific features separating lichen sclerosus from a morphea overlap and both entities often are classified by clinical presentation, lichen sclerosus demonstrates epidermal atrophy, follicular plugging, homogenized collagen in the upper dermis with dermal edema, and lichenoid lymphocytic infiltrate (Figure 2).¹ Extragenital lesions in particular also have been noted to have more epidermal atrophy and decreased rete ridges.²

First-line treatment of lichen sclerosus includes topical corticosteroids with emollients for supportive therapy. A topical calcineurin inhibitor such as tacrolimus should be considered for patients who do not respond to corticosteroid therapy or in cases in which corticosteroid therapy is contraindicated to avoid steroid-induced glaucoma or undesirable skin atrophy and hypopigmentation.² A collaborative approach including dermatology and internal medicine can help identify a systemic or multisystem process.

 

To the Editor:

Lichen sclerosus is a chronic inflammatory skin disease of unknown cause that predominantly affects the anogenital region, but isolated extragenital lesions occur in 6% to 15% of patients. The buttocks, thighs, neck, shoulder, upper torso, and wrists most commonly are involved; the face rarely is affected.^1,2 Although the etiology of lichen sclerosus remains undetermined, there is growing evidence that autoimmunity may play a role.¹ Lichen sclerosus more commonly is seen in women, and the disease can present at any age, with a bimodal onset in prepubertal children and in postmenopausal women and men in the fourth decade of life.^1-3 A PubMed search of articles indexed for MEDLINE using the terms lichen and eyelid and manually screened revealed 6 cases of lichen sclerosus involving the eyelid.^2-4 We describe a case of lichen sclerosus involving the eyelid and its histopathology.

A 45-year-old woman was referred to dermatology for evaluation of a right lower eyelid lesion of 3 months’ duration. She first noted a small white patch under the eyelid that had doubled in size and felt firm without bleeding or ulceration. Her medical history was unremarkable, and there was no history of ophthalmic conditions, autoimmune disease, trauma, or cancer. An ophthalmic examination was normal, except for a 20×8-mm, flat, depigmented, firm papule with scalloped borders involving the right lower eyelid margin and extending inferiorly without evidence of madarosis or ulceration (Figure 1). She underwent an incisional biopsy that revealed the diagnosis of lichen sclerosus et atrophicus (Figure 2). A full dermatologic evaluation included a genital examination and did not reveal any additional lesions. Tacrolimus ointment was started to avoid the need for long-term use of periocular steroids and their complications.

Extragenital lichen sclerosus typically is asymptomatic and only rarely presents with pruritus, in contrast to genital lichen sclerosus, which characteristically involves pruritus and dyspareunia. Although eyelid involvement is rare, ophthalmic manifestations of lichen sclerosus have included lid notching, ectropion, acquired Brown syndrome, and associated keratoconjunctivitis sicca.^3-5 It characteristically appears as a well-demarcated hypopigmented papule. The differential diagnosis for a hypopigmented papule also includes amelanotic melanoma, basal cell carcinoma, vitiligo, tinea versicolor, lichen simplex chronicus, lichen planus, morphea (localized scleroderma), and systemic scleroderma with eyelid involvement.^1,5

Differentiating lichen sclerosus from these conditions is of importance, as some of them can have notable morbidity and/or mortality. Of all the autoimmune connective tissue disorders, systemic sclerosus has the highest disease-specific mortality.⁶ Morphea, on the other hand, can have considerable morbidity. Morphea involving the head and neck notably increases the risk for neurologic complications such as seizures or central nervous system vasculitis as well as ocular complications such as anterior uveitis.⁶ Of note, genital lichen sclerosus carries an increased risk for squamous cell carcinoma and verrucous carcinoma; however, there have been no reported cases of malignant transformation with extragenital lesions.²

Histopathology is useful to distinguish among these entities. Although there are no specific features separating lichen sclerosus from a morphea overlap and both entities often are classified by clinical presentation, lichen sclerosus demonstrates epidermal atrophy, follicular plugging, homogenized collagen in the upper dermis with dermal edema, and lichenoid lymphocytic infiltrate (Figure 2).¹ Extragenital lesions in particular also have been noted to have more epidermal atrophy and decreased rete ridges.²

First-line treatment of lichen sclerosus includes topical corticosteroids with emollients for supportive therapy. A topical calcineurin inhibitor such as tacrolimus should be considered for patients who do not respond to corticosteroid therapy or in cases in which corticosteroid therapy is contraindicated to avoid steroid-induced glaucoma or undesirable skin atrophy and hypopigmentation.² A collaborative approach including dermatology and internal medicine can help identify a systemic or multisystem process.

The Diagnosis: Clonal Melanoacanthoma 

Melanoacanthoma (MA) is an extremely rare, benign, epidermal tumor histologically characterized by keratinocytes and large, pigmented, dendritic melanocytes. These lesions are loosely related to seborrheic keratoses, and the term was first coined by Mishima and Pinkus¹ in 1960. It is estimated that the lesion occurs in only 5 of 500,000 individuals and tends to occur in older, light-skinned individuals.² The majority are slow growing and are present on the head, neck, or upper extremities; however, similar lesions also have been reported on the oral mucosa.³ Melanoacanthomas range in size from 2×2 to 15×15 cm; are clinically pigmented; and present as either a papule, plaque, nodule, or horn.² 

Classic histologic findings of MA include papillomatosis, acanthosis, and hyperkeratosis with heavily pigmented dendritic melanocytes diffusely dispersed throughout all layers of the seborrheic keratosis-like epidermis.³ Other features include keratin-filled pseudocysts, Langerhans cells, reactive spindling of keratinocytes, and an inflammatory infiltrate. In our case, the classic histologic findings also were architecturally arranged in oval to round clones within the epidermis (quiz images 1 and 2). A MART-1 (melanoma antigen recognized by T cells) immunostain was obtained that highlighted the numerous but benign-appearing, dendritic melanocytes (quiz image 2 [inset]). A dual MART-1/Ki67 immunostain later was obtained and demonstrated a negligible proliferation index within the dendritic melanocytes. Therefore, the diagnosis of clonal MA was rendered. This formation of epidermal clones also is called the Borst-Jadassohn phenomenon, which rarely occurs in MAs. This subtype is important to recognize because the clonal pattern can more closely mimic malignant neoplasms such as melanoma.  

Hidroacanthoma simplex is an intraepidermal variant of eccrine poroma. It is a rare entity that typically occurs in the extremities of women as a hyperkeratotic plaque. These typically clonal epidermal tumors may be heavily pigmented and rarely contain dendritic melanocytes; therefore, they may be confused with MA. However, classic histology will reveal an intraepidermal clonal proliferation of bland, monotonous, cuboidal cells with ample pink cytoplasm, as well as occasional cuticle-lined ducts (Figure 1).⁴ These ducts will highlight with carcinoembryonic antigen and epithelial membrane antigen immunostaining.  

Malignant melanoma typically presents as a growing pigmented lesion and therefore can clinically mimic MA. Histologically, MA could be confused with melanoma due to the increased number of melanocytes plus the appearance of pagetoid spread resulting from the diffuse presence of melanocytes throughout the neoplasm. However, histologic assessment of melanoma should reveal cytologic atypia such as nuclear enlargement, hyperchromasia, molding, pleomorphism, and mitotic activity (Figure 2). Architectural atypia such as poor lateral circumscription of melanocytes, confluence and pagetoid spread of nondendritic atypical junctional melanocytes, production of pigment in deep dermal nests of melanocytes, and lack of maturation and dispersion of dermal melanocytes also should be seen.⁵ Unlike a melanocytic neoplasm, true melanocytic nests are not seen in MA, and the melanocytes are bland, normal-appearing but heavily pigmented, dendritic melanocytes. Electron microscopy has shown a defect in the transfer of melanin from these highly dendritic melanocytes to the keratinocytes.⁶  

Similar to melanoma, seborrheic keratosis presents as a pigmented growing lesion; therefore, definitive diagnosis often is achieved via skin biopsy. Classic histologic findings include acanthotic or exophytic epidermal growth with a dome-shaped configuration containing multiple cornified hornlike cysts (Figure 3).⁷ Multiple keratin plugs and variably sized concentric keratin islands are common features. There may be varying degrees of melanin pigment deposition among the proliferating cells, and clonal formation may occur. Melanocyte-specific special stains and immunostains can be used to differentiate MA from seborrheic keratosis by highlighting numerous dendritic melanocytes diffusely spread throughout the epidermis in MA vs a normal distribution of occasional junctional melanocytes in seborrheic keratosis.^2,8  

Squamous cell carcinoma in situ presents histologically with cytologically atypical keratinocytes encompassing the full thickness of the epidermis and sometimes crushing the basement membrane zone (Figure 4). There is a loss of the granular layer and overlying parakeratosis that often spares the adnexal ostial epithelium.⁹ Clonal formation can occur as well as increased pigment production. In comparison, bland keratinocytes are seen in MA.  

Establishing the diagnosis of MA based on clinical features alone can be difficult. Dermoscopy can prove to be useful and typically will show a sunburst pattern with ridges and fissures.² However, seborrheic keratoses and melanomas can have similar dermoscopic findings¹⁰; therefore, a biopsy often is necessary to establish the diagnosis. 

The Diagnosis: Clonal Melanoacanthoma 

Melanoacanthoma (MA) is an extremely rare, benign, epidermal tumor histologically characterized by keratinocytes and large, pigmented, dendritic melanocytes. These lesions are loosely related to seborrheic keratoses, and the term was first coined by Mishima and Pinkus¹ in 1960. It is estimated that the lesion occurs in only 5 of 500,000 individuals and tends to occur in older, light-skinned individuals.² The majority are slow growing and are present on the head, neck, or upper extremities; however, similar lesions also have been reported on the oral mucosa.³ Melanoacanthomas range in size from 2×2 to 15×15 cm; are clinically pigmented; and present as either a papule, plaque, nodule, or horn.² 

Classic histologic findings of MA include papillomatosis, acanthosis, and hyperkeratosis with heavily pigmented dendritic melanocytes diffusely dispersed throughout all layers of the seborrheic keratosis-like epidermis.³ Other features include keratin-filled pseudocysts, Langerhans cells, reactive spindling of keratinocytes, and an inflammatory infiltrate. In our case, the classic histologic findings also were architecturally arranged in oval to round clones within the epidermis (quiz images 1 and 2). A MART-1 (melanoma antigen recognized by T cells) immunostain was obtained that highlighted the numerous but benign-appearing, dendritic melanocytes (quiz image 2 [inset]). A dual MART-1/Ki67 immunostain later was obtained and demonstrated a negligible proliferation index within the dendritic melanocytes. Therefore, the diagnosis of clonal MA was rendered. This formation of epidermal clones also is called the Borst-Jadassohn phenomenon, which rarely occurs in MAs. This subtype is important to recognize because the clonal pattern can more closely mimic malignant neoplasms such as melanoma.  

Hidroacanthoma simplex is an intraepidermal variant of eccrine poroma. It is a rare entity that typically occurs in the extremities of women as a hyperkeratotic plaque. These typically clonal epidermal tumors may be heavily pigmented and rarely contain dendritic melanocytes; therefore, they may be confused with MA. However, classic histology will reveal an intraepidermal clonal proliferation of bland, monotonous, cuboidal cells with ample pink cytoplasm, as well as occasional cuticle-lined ducts (Figure 1).⁴ These ducts will highlight with carcinoembryonic antigen and epithelial membrane antigen immunostaining.  

Malignant melanoma typically presents as a growing pigmented lesion and therefore can clinically mimic MA. Histologically, MA could be confused with melanoma due to the increased number of melanocytes plus the appearance of pagetoid spread resulting from the diffuse presence of melanocytes throughout the neoplasm. However, histologic assessment of melanoma should reveal cytologic atypia such as nuclear enlargement, hyperchromasia, molding, pleomorphism, and mitotic activity (Figure 2). Architectural atypia such as poor lateral circumscription of melanocytes, confluence and pagetoid spread of nondendritic atypical junctional melanocytes, production of pigment in deep dermal nests of melanocytes, and lack of maturation and dispersion of dermal melanocytes also should be seen.⁵ Unlike a melanocytic neoplasm, true melanocytic nests are not seen in MA, and the melanocytes are bland, normal-appearing but heavily pigmented, dendritic melanocytes. Electron microscopy has shown a defect in the transfer of melanin from these highly dendritic melanocytes to the keratinocytes.⁶  

Similar to melanoma, seborrheic keratosis presents as a pigmented growing lesion; therefore, definitive diagnosis often is achieved via skin biopsy. Classic histologic findings include acanthotic or exophytic epidermal growth with a dome-shaped configuration containing multiple cornified hornlike cysts (Figure 3).⁷ Multiple keratin plugs and variably sized concentric keratin islands are common features. There may be varying degrees of melanin pigment deposition among the proliferating cells, and clonal formation may occur. Melanocyte-specific special stains and immunostains can be used to differentiate MA from seborrheic keratosis by highlighting numerous dendritic melanocytes diffusely spread throughout the epidermis in MA vs a normal distribution of occasional junctional melanocytes in seborrheic keratosis.^2,8  

Squamous cell carcinoma in situ presents histologically with cytologically atypical keratinocytes encompassing the full thickness of the epidermis and sometimes crushing the basement membrane zone (Figure 4). There is a loss of the granular layer and overlying parakeratosis that often spares the adnexal ostial epithelium.⁹ Clonal formation can occur as well as increased pigment production. In comparison, bland keratinocytes are seen in MA.  

Establishing the diagnosis of MA based on clinical features alone can be difficult. Dermoscopy can prove to be useful and typically will show a sunburst pattern with ridges and fissures.² However, seborrheic keratoses and melanomas can have similar dermoscopic findings¹⁰; therefore, a biopsy often is necessary to establish the diagnosis. 

The Diagnosis: Clonal Melanoacanthoma 

Melanoacanthoma (MA) is an extremely rare, benign, epidermal tumor histologically characterized by keratinocytes and large, pigmented, dendritic melanocytes. These lesions are loosely related to seborrheic keratoses, and the term was first coined by Mishima and Pinkus¹ in 1960. It is estimated that the lesion occurs in only 5 of 500,000 individuals and tends to occur in older, light-skinned individuals.² The majority are slow growing and are present on the head, neck, or upper extremities; however, similar lesions also have been reported on the oral mucosa.³ Melanoacanthomas range in size from 2×2 to 15×15 cm; are clinically pigmented; and present as either a papule, plaque, nodule, or horn.² 

Classic histologic findings of MA include papillomatosis, acanthosis, and hyperkeratosis with heavily pigmented dendritic melanocytes diffusely dispersed throughout all layers of the seborrheic keratosis-like epidermis.³ Other features include keratin-filled pseudocysts, Langerhans cells, reactive spindling of keratinocytes, and an inflammatory infiltrate. In our case, the classic histologic findings also were architecturally arranged in oval to round clones within the epidermis (quiz images 1 and 2). A MART-1 (melanoma antigen recognized by T cells) immunostain was obtained that highlighted the numerous but benign-appearing, dendritic melanocytes (quiz image 2 [inset]). A dual MART-1/Ki67 immunostain later was obtained and demonstrated a negligible proliferation index within the dendritic melanocytes. Therefore, the diagnosis of clonal MA was rendered. This formation of epidermal clones also is called the Borst-Jadassohn phenomenon, which rarely occurs in MAs. This subtype is important to recognize because the clonal pattern can more closely mimic malignant neoplasms such as melanoma.  

Hidroacanthoma simplex is an intraepidermal variant of eccrine poroma. It is a rare entity that typically occurs in the extremities of women as a hyperkeratotic plaque. These typically clonal epidermal tumors may be heavily pigmented and rarely contain dendritic melanocytes; therefore, they may be confused with MA. However, classic histology will reveal an intraepidermal clonal proliferation of bland, monotonous, cuboidal cells with ample pink cytoplasm, as well as occasional cuticle-lined ducts (Figure 1).⁴ These ducts will highlight with carcinoembryonic antigen and epithelial membrane antigen immunostaining.  

Malignant melanoma typically presents as a growing pigmented lesion and therefore can clinically mimic MA. Histologically, MA could be confused with melanoma due to the increased number of melanocytes plus the appearance of pagetoid spread resulting from the diffuse presence of melanocytes throughout the neoplasm. However, histologic assessment of melanoma should reveal cytologic atypia such as nuclear enlargement, hyperchromasia, molding, pleomorphism, and mitotic activity (Figure 2). Architectural atypia such as poor lateral circumscription of melanocytes, confluence and pagetoid spread of nondendritic atypical junctional melanocytes, production of pigment in deep dermal nests of melanocytes, and lack of maturation and dispersion of dermal melanocytes also should be seen.⁵ Unlike a melanocytic neoplasm, true melanocytic nests are not seen in MA, and the melanocytes are bland, normal-appearing but heavily pigmented, dendritic melanocytes. Electron microscopy has shown a defect in the transfer of melanin from these highly dendritic melanocytes to the keratinocytes.⁶  

Similar to melanoma, seborrheic keratosis presents as a pigmented growing lesion; therefore, definitive diagnosis often is achieved via skin biopsy. Classic histologic findings include acanthotic or exophytic epidermal growth with a dome-shaped configuration containing multiple cornified hornlike cysts (Figure 3).⁷ Multiple keratin plugs and variably sized concentric keratin islands are common features. There may be varying degrees of melanin pigment deposition among the proliferating cells, and clonal formation may occur. Melanocyte-specific special stains and immunostains can be used to differentiate MA from seborrheic keratosis by highlighting numerous dendritic melanocytes diffusely spread throughout the epidermis in MA vs a normal distribution of occasional junctional melanocytes in seborrheic keratosis.^2,8  

Squamous cell carcinoma in situ presents histologically with cytologically atypical keratinocytes encompassing the full thickness of the epidermis and sometimes crushing the basement membrane zone (Figure 4). There is a loss of the granular layer and overlying parakeratosis that often spares the adnexal ostial epithelium.⁹ Clonal formation can occur as well as increased pigment production. In comparison, bland keratinocytes are seen in MA.  

Establishing the diagnosis of MA based on clinical features alone can be difficult. Dermoscopy can prove to be useful and typically will show a sunburst pattern with ridges and fissures.² However, seborrheic keratoses and melanomas can have similar dermoscopic findings¹⁰; therefore, a biopsy often is necessary to establish the diagnosis. 

The Diagnosis: Primary Cutaneous γδ T-cell Lymphoma

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a distinct entity that can be confused with other types of cutaneous T-cell lymphomas. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal.¹ Primary cutaneous γδ T-cell lymphoma represents less than 1% of all cutaneous T-cell lymphomas.² Diagnosis and treatment remain challenging. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection on clinical examination; biopsy establishes the diagnosis. Typical findings include a cytotoxic phenotype, variable epidermotropism, dermal and subcutaneous involvement, and loss of CD4 and often CD8 expression. Testing for Epstein-Barr virus expression yields negative results. The neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are T-cell intracellular antigen-1 (TIA-1) and granzyme positive.¹

Immunohistochemistry failed to reveal CD8, CD56, granzyme, or T-cell intracellular antigen-1 staining of neoplastic cells in our patient but stained diffusely positive with CD3 and CD4. A CD20 stain decorated only a few dermal cells. The patient’s skin lesions continued to enlarge, and the massive lymphadenopathy made breathing difficult. Computed tomography revealed diffuse systemic involvement. An axillary lymph node biopsy revealed sinusoids with complete diffuse effacement of architecture as well as frequent mitotic figures and karyorrhectic debris (Figure 1A). Negative staining for T-cell receptor beta-F1 of the axillary lymph node biopsy and clonal rearrangement of the T-cell receptor gamma chain supported the diagnosis of PCGDTL. Nuclear staining for Epstein-Barr virus–encoded RNA was negative. Human T-cell leukemia virus type 1 antibodies and polymerase chain reaction also were negative. Flow cytometry demonstrated an atypical population of CD3⁺, CD4⁺, and CD7− γδ T lymphocytes, further supporting the diagnosis of lymphoma.

The median life expectancy for patients with dermal or subcutaneous PCGDTL is 10 to 15 months after diagnosis.³ The 5-year life expectancy for PCGDTL is approximately 11%.² Limited treatment options contribute to the poor outcome. Chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and EPOCH (etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) have yielded inconsistent results. Stem cell transplant has been tried in progressive disease and also has yielded mixed results.² Brentuximab is indicated for individuals whose tumors express CD30.⁴ Associated hemophagic lymphohistiocytosis portends a poor prognosis.⁵

Despite treatment with etoposide, vincristine, doxorubicin, and high-dose oral steroids, our patient developed progressive difficulty breathing, stridor, kidney injury, and anemia. Our patient died less than 1 month after diagnosis—after only 1 round of chemotherapy—secondary to progressive disease and an uncontrollable gastrointestinal tract bleed. The leonine facies (Figure 1B) encountered in our patient can raise a differential diagnosis that includes infectious as well as neoplastic etiologies; however, most infectious etiologies associated with leonine facies manifest in a chronic fashion rather than with a sudden eruption, as noted in our patient.

Leprosy is caused by Mycobacterium leprae, a grampositive bacillus. The condition manifests across a spectrum, with the poles being tuberculoid and lepromatous, and borderline variants in between.^6-8 Lepromatous leprosy arises in individuals who are unable to mount cellular immunity against M leprae secondary to anergy.⁶ Lepromatous leprosy often presents with numerous papules and nodules. Aside from cutaneous manifestations, lepromatous leprosy has a predilection for peripheral nerves and specifically Schwann cells. Histologically, biopsy reveals a flat epidermis and a cell-free subepidermal grenz zone. Within the dermis, there is a diffuse histiocytic infiltrate that typically is not centered around nerves (Figure 2).^6,7 Mycobacterium leprae can appear scattered throughout or clustered in globi. Mycobacterium leprae stains red with Ziehl-Neelsen or Wade-Fite stains.^6,7 Immunohistochemistry reveals a CD4⁺ helper T cell (TH2) predominance, supported by the increased expression of type 2 reaction cytokines such as IL-4, IL-5, IL-10, and IL-13.⁸

Diffuse large B-cell lymphoma (DLBCL) embodies 10% to 20% of all primary cutaneous lymphomas; it is more prevalent in older adults (age range, 70–82 years) and women. Clinically, DLBCL presents as either single or multiple rapidly progressing nodules or plaques, usually violaceous or blue-red in color.^9,10 The most common area of presentation is on the legs, though it also can surface at other sites.⁹ On histology, DLBCL has clearly malignant features including frequent mitotic figures, large immunoblasts, and involvement throughout the dermis as well as perivascularly (Figure 3). Spindle-shaped cells and anaplastic features can be present. Immunohistochemically, DLBCL stains strongly positive for CD20 and B-cell lymphoma 2 (Bcl-2) along with other pan–B-cell markers.^9-11 The aggressive leg type of DLBCL stains positively for multiple myeloma oncogene 1 (MUM-1).^9,11

Cutaneous metastatic adenocarcinoma from internal malignancies occurs in approximately 5% of cancer patients with metastatic spread.¹² Most of these cutaneous lesions develop in close proximity to the primary tumor such as on the trunk, head, or neck. All cutaneous metastases carry a poor prognosis. Clinical presentation can vary greatly, ranging from painless, firm, or elastic nodules to lesions that mimic inflammatory skin conditions such as erysipelas or scleroderma. The majority of these metastases develop as painless firm nodules that are flesh colored, pink, red-brown, or purple.^12,13 The histopathology of metastatic adenocarcinoma demonstrates an infiltrative nodular appearance, though there rarely are well-circumscribed nodules found.¹³ The lesion originates in the dermis or subcutaneous tissue. It is a glandulartype lesion that may reflect the tissue of the primary tumor (Figure 4).^12,14 Immunohistochemical stains likely will remain consistent with those of the primary tumor, which is not always the case.¹⁴

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy of epithelial and neuroendocrine origin, first described as trabecular carcinoma due to the arrangement of tumor resembling cancellous bone.^15,16 Merkel cells are mechanoreceptors found near nerve terminals.¹⁷ Approximately 80% of MCCs are associated with Merkel cell polyomavirus, which is a small, double-stranded DNA virus with an icosahedral capsid.^17,18 Merkel cell polyomavirus–positive cases of MCC tend to have a better prognosis. In Merkel cell polyomavirus–negative MCC, there is an association with UV damage and increased chromosomal aberrations.¹⁸ Merkel cell carcinoma is known for its high rate of recurrence as well as local and distant metastasis. Nodal involvement is the most important prognostic indicator.¹⁵ Clinically, MCC is associated with the AEIOU mnemonic (asymptomatic, expanding rapidly, immunosuppression, older than 50 years, UV exposed/fair skin).^15-17 Lesions appear as red-blue papules on sun-exposed skin and usually are smaller than 2 cm by their greatest dimension. On histopathology, MCC demonstrates small, round, blue cells arranged in sheets or nests originating in the dermis and occasionally can infiltrate the subcutis and lymphovascular surroundings (Figure 5).^16-19 Cells have scant eosinophilic cytoplasm and may have fine granular chromatin. Numerous mitotic figures and apoptotic cells also are present. On immunohistochemistry, these cells will stain positive for cytokeratin AE1/AE3, anticytokeratin (CAM 5.2), CK20, and CD56. Due to their neuroendocrine derivation, they also are commonly synaptophysin, neuron-specific enolase, and chromogranin A positive. Notably, MCC will stain negative for leukocyte common antigen, CD20, CD3, CD34, and thyroid transcription factor 1 (TTF-1).^16,17

Primary cutaneous γδ T-cell lymphoma can be difficult to diagnose and requires urgent treatment. Clinicians and dermatopathologists need to work together to establish the diagnosis. There is a high mortality rate associated with PCGDTL, making prompt recognition and timely treatment critical. Acknowledgments—Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

 

Acknowledgments
Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

The Diagnosis: Primary Cutaneous γδ T-cell Lymphoma

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a distinct entity that can be confused with other types of cutaneous T-cell lymphomas. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal.¹ Primary cutaneous γδ T-cell lymphoma represents less than 1% of all cutaneous T-cell lymphomas.² Diagnosis and treatment remain challenging. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection on clinical examination; biopsy establishes the diagnosis. Typical findings include a cytotoxic phenotype, variable epidermotropism, dermal and subcutaneous involvement, and loss of CD4 and often CD8 expression. Testing for Epstein-Barr virus expression yields negative results. The neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are T-cell intracellular antigen-1 (TIA-1) and granzyme positive.¹

Immunohistochemistry failed to reveal CD8, CD56, granzyme, or T-cell intracellular antigen-1 staining of neoplastic cells in our patient but stained diffusely positive with CD3 and CD4. A CD20 stain decorated only a few dermal cells. The patient’s skin lesions continued to enlarge, and the massive lymphadenopathy made breathing difficult. Computed tomography revealed diffuse systemic involvement. An axillary lymph node biopsy revealed sinusoids with complete diffuse effacement of architecture as well as frequent mitotic figures and karyorrhectic debris (Figure 1A). Negative staining for T-cell receptor beta-F1 of the axillary lymph node biopsy and clonal rearrangement of the T-cell receptor gamma chain supported the diagnosis of PCGDTL. Nuclear staining for Epstein-Barr virus–encoded RNA was negative. Human T-cell leukemia virus type 1 antibodies and polymerase chain reaction also were negative. Flow cytometry demonstrated an atypical population of CD3⁺, CD4⁺, and CD7− γδ T lymphocytes, further supporting the diagnosis of lymphoma.

The median life expectancy for patients with dermal or subcutaneous PCGDTL is 10 to 15 months after diagnosis.³ The 5-year life expectancy for PCGDTL is approximately 11%.² Limited treatment options contribute to the poor outcome. Chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and EPOCH (etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) have yielded inconsistent results. Stem cell transplant has been tried in progressive disease and also has yielded mixed results.² Brentuximab is indicated for individuals whose tumors express CD30.⁴ Associated hemophagic lymphohistiocytosis portends a poor prognosis.⁵

Despite treatment with etoposide, vincristine, doxorubicin, and high-dose oral steroids, our patient developed progressive difficulty breathing, stridor, kidney injury, and anemia. Our patient died less than 1 month after diagnosis—after only 1 round of chemotherapy—secondary to progressive disease and an uncontrollable gastrointestinal tract bleed. The leonine facies (Figure 1B) encountered in our patient can raise a differential diagnosis that includes infectious as well as neoplastic etiologies; however, most infectious etiologies associated with leonine facies manifest in a chronic fashion rather than with a sudden eruption, as noted in our patient.

Leprosy is caused by Mycobacterium leprae, a grampositive bacillus. The condition manifests across a spectrum, with the poles being tuberculoid and lepromatous, and borderline variants in between.^6-8 Lepromatous leprosy arises in individuals who are unable to mount cellular immunity against M leprae secondary to anergy.⁶ Lepromatous leprosy often presents with numerous papules and nodules. Aside from cutaneous manifestations, lepromatous leprosy has a predilection for peripheral nerves and specifically Schwann cells. Histologically, biopsy reveals a flat epidermis and a cell-free subepidermal grenz zone. Within the dermis, there is a diffuse histiocytic infiltrate that typically is not centered around nerves (Figure 2).^6,7 Mycobacterium leprae can appear scattered throughout or clustered in globi. Mycobacterium leprae stains red with Ziehl-Neelsen or Wade-Fite stains.^6,7 Immunohistochemistry reveals a CD4⁺ helper T cell (TH2) predominance, supported by the increased expression of type 2 reaction cytokines such as IL-4, IL-5, IL-10, and IL-13.⁸

Diffuse large B-cell lymphoma (DLBCL) embodies 10% to 20% of all primary cutaneous lymphomas; it is more prevalent in older adults (age range, 70–82 years) and women. Clinically, DLBCL presents as either single or multiple rapidly progressing nodules or plaques, usually violaceous or blue-red in color.^9,10 The most common area of presentation is on the legs, though it also can surface at other sites.⁹ On histology, DLBCL has clearly malignant features including frequent mitotic figures, large immunoblasts, and involvement throughout the dermis as well as perivascularly (Figure 3). Spindle-shaped cells and anaplastic features can be present. Immunohistochemically, DLBCL stains strongly positive for CD20 and B-cell lymphoma 2 (Bcl-2) along with other pan–B-cell markers.^9-11 The aggressive leg type of DLBCL stains positively for multiple myeloma oncogene 1 (MUM-1).^9,11

Cutaneous metastatic adenocarcinoma from internal malignancies occurs in approximately 5% of cancer patients with metastatic spread.¹² Most of these cutaneous lesions develop in close proximity to the primary tumor such as on the trunk, head, or neck. All cutaneous metastases carry a poor prognosis. Clinical presentation can vary greatly, ranging from painless, firm, or elastic nodules to lesions that mimic inflammatory skin conditions such as erysipelas or scleroderma. The majority of these metastases develop as painless firm nodules that are flesh colored, pink, red-brown, or purple.^12,13 The histopathology of metastatic adenocarcinoma demonstrates an infiltrative nodular appearance, though there rarely are well-circumscribed nodules found.¹³ The lesion originates in the dermis or subcutaneous tissue. It is a glandulartype lesion that may reflect the tissue of the primary tumor (Figure 4).^12,14 Immunohistochemical stains likely will remain consistent with those of the primary tumor, which is not always the case.¹⁴

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy of epithelial and neuroendocrine origin, first described as trabecular carcinoma due to the arrangement of tumor resembling cancellous bone.^15,16 Merkel cells are mechanoreceptors found near nerve terminals.¹⁷ Approximately 80% of MCCs are associated with Merkel cell polyomavirus, which is a small, double-stranded DNA virus with an icosahedral capsid.^17,18 Merkel cell polyomavirus–positive cases of MCC tend to have a better prognosis. In Merkel cell polyomavirus–negative MCC, there is an association with UV damage and increased chromosomal aberrations.¹⁸ Merkel cell carcinoma is known for its high rate of recurrence as well as local and distant metastasis. Nodal involvement is the most important prognostic indicator.¹⁵ Clinically, MCC is associated with the AEIOU mnemonic (asymptomatic, expanding rapidly, immunosuppression, older than 50 years, UV exposed/fair skin).^15-17 Lesions appear as red-blue papules on sun-exposed skin and usually are smaller than 2 cm by their greatest dimension. On histopathology, MCC demonstrates small, round, blue cells arranged in sheets or nests originating in the dermis and occasionally can infiltrate the subcutis and lymphovascular surroundings (Figure 5).^16-19 Cells have scant eosinophilic cytoplasm and may have fine granular chromatin. Numerous mitotic figures and apoptotic cells also are present. On immunohistochemistry, these cells will stain positive for cytokeratin AE1/AE3, anticytokeratin (CAM 5.2), CK20, and CD56. Due to their neuroendocrine derivation, they also are commonly synaptophysin, neuron-specific enolase, and chromogranin A positive. Notably, MCC will stain negative for leukocyte common antigen, CD20, CD3, CD34, and thyroid transcription factor 1 (TTF-1).^16,17

Primary cutaneous γδ T-cell lymphoma can be difficult to diagnose and requires urgent treatment. Clinicians and dermatopathologists need to work together to establish the diagnosis. There is a high mortality rate associated with PCGDTL, making prompt recognition and timely treatment critical. Acknowledgments—Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

 

Acknowledgments
Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

The Diagnosis: Primary Cutaneous γδ T-cell Lymphoma

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a distinct entity that can be confused with other types of cutaneous T-cell lymphomas. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal.¹ Primary cutaneous γδ T-cell lymphoma represents less than 1% of all cutaneous T-cell lymphomas.² Diagnosis and treatment remain challenging. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection on clinical examination; biopsy establishes the diagnosis. Typical findings include a cytotoxic phenotype, variable epidermotropism, dermal and subcutaneous involvement, and loss of CD4 and often CD8 expression. Testing for Epstein-Barr virus expression yields negative results. The neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are T-cell intracellular antigen-1 (TIA-1) and granzyme positive.¹

Immunohistochemistry failed to reveal CD8, CD56, granzyme, or T-cell intracellular antigen-1 staining of neoplastic cells in our patient but stained diffusely positive with CD3 and CD4. A CD20 stain decorated only a few dermal cells. The patient’s skin lesions continued to enlarge, and the massive lymphadenopathy made breathing difficult. Computed tomography revealed diffuse systemic involvement. An axillary lymph node biopsy revealed sinusoids with complete diffuse effacement of architecture as well as frequent mitotic figures and karyorrhectic debris (Figure 1A). Negative staining for T-cell receptor beta-F1 of the axillary lymph node biopsy and clonal rearrangement of the T-cell receptor gamma chain supported the diagnosis of PCGDTL. Nuclear staining for Epstein-Barr virus–encoded RNA was negative. Human T-cell leukemia virus type 1 antibodies and polymerase chain reaction also were negative. Flow cytometry demonstrated an atypical population of CD3⁺, CD4⁺, and CD7− γδ T lymphocytes, further supporting the diagnosis of lymphoma.

The median life expectancy for patients with dermal or subcutaneous PCGDTL is 10 to 15 months after diagnosis.³ The 5-year life expectancy for PCGDTL is approximately 11%.² Limited treatment options contribute to the poor outcome. Chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and EPOCH (etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) have yielded inconsistent results. Stem cell transplant has been tried in progressive disease and also has yielded mixed results.² Brentuximab is indicated for individuals whose tumors express CD30.⁴ Associated hemophagic lymphohistiocytosis portends a poor prognosis.⁵

Despite treatment with etoposide, vincristine, doxorubicin, and high-dose oral steroids, our patient developed progressive difficulty breathing, stridor, kidney injury, and anemia. Our patient died less than 1 month after diagnosis—after only 1 round of chemotherapy—secondary to progressive disease and an uncontrollable gastrointestinal tract bleed. The leonine facies (Figure 1B) encountered in our patient can raise a differential diagnosis that includes infectious as well as neoplastic etiologies; however, most infectious etiologies associated with leonine facies manifest in a chronic fashion rather than with a sudden eruption, as noted in our patient.

Leprosy is caused by Mycobacterium leprae, a grampositive bacillus. The condition manifests across a spectrum, with the poles being tuberculoid and lepromatous, and borderline variants in between.^6-8 Lepromatous leprosy arises in individuals who are unable to mount cellular immunity against M leprae secondary to anergy.⁶ Lepromatous leprosy often presents with numerous papules and nodules. Aside from cutaneous manifestations, lepromatous leprosy has a predilection for peripheral nerves and specifically Schwann cells. Histologically, biopsy reveals a flat epidermis and a cell-free subepidermal grenz zone. Within the dermis, there is a diffuse histiocytic infiltrate that typically is not centered around nerves (Figure 2).^6,7 Mycobacterium leprae can appear scattered throughout or clustered in globi. Mycobacterium leprae stains red with Ziehl-Neelsen or Wade-Fite stains.^6,7 Immunohistochemistry reveals a CD4⁺ helper T cell (TH2) predominance, supported by the increased expression of type 2 reaction cytokines such as IL-4, IL-5, IL-10, and IL-13.⁸

Diffuse large B-cell lymphoma (DLBCL) embodies 10% to 20% of all primary cutaneous lymphomas; it is more prevalent in older adults (age range, 70–82 years) and women. Clinically, DLBCL presents as either single or multiple rapidly progressing nodules or plaques, usually violaceous or blue-red in color.^9,10 The most common area of presentation is on the legs, though it also can surface at other sites.⁹ On histology, DLBCL has clearly malignant features including frequent mitotic figures, large immunoblasts, and involvement throughout the dermis as well as perivascularly (Figure 3). Spindle-shaped cells and anaplastic features can be present. Immunohistochemically, DLBCL stains strongly positive for CD20 and B-cell lymphoma 2 (Bcl-2) along with other pan–B-cell markers.^9-11 The aggressive leg type of DLBCL stains positively for multiple myeloma oncogene 1 (MUM-1).^9,11

Cutaneous metastatic adenocarcinoma from internal malignancies occurs in approximately 5% of cancer patients with metastatic spread.¹² Most of these cutaneous lesions develop in close proximity to the primary tumor such as on the trunk, head, or neck. All cutaneous metastases carry a poor prognosis. Clinical presentation can vary greatly, ranging from painless, firm, or elastic nodules to lesions that mimic inflammatory skin conditions such as erysipelas or scleroderma. The majority of these metastases develop as painless firm nodules that are flesh colored, pink, red-brown, or purple.^12,13 The histopathology of metastatic adenocarcinoma demonstrates an infiltrative nodular appearance, though there rarely are well-circumscribed nodules found.¹³ The lesion originates in the dermis or subcutaneous tissue. It is a glandulartype lesion that may reflect the tissue of the primary tumor (Figure 4).^12,14 Immunohistochemical stains likely will remain consistent with those of the primary tumor, which is not always the case.¹⁴

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy of epithelial and neuroendocrine origin, first described as trabecular carcinoma due to the arrangement of tumor resembling cancellous bone.^15,16 Merkel cells are mechanoreceptors found near nerve terminals.¹⁷ Approximately 80% of MCCs are associated with Merkel cell polyomavirus, which is a small, double-stranded DNA virus with an icosahedral capsid.^17,18 Merkel cell polyomavirus–positive cases of MCC tend to have a better prognosis. In Merkel cell polyomavirus–negative MCC, there is an association with UV damage and increased chromosomal aberrations.¹⁸ Merkel cell carcinoma is known for its high rate of recurrence as well as local and distant metastasis. Nodal involvement is the most important prognostic indicator.¹⁵ Clinically, MCC is associated with the AEIOU mnemonic (asymptomatic, expanding rapidly, immunosuppression, older than 50 years, UV exposed/fair skin).^15-17 Lesions appear as red-blue papules on sun-exposed skin and usually are smaller than 2 cm by their greatest dimension. On histopathology, MCC demonstrates small, round, blue cells arranged in sheets or nests originating in the dermis and occasionally can infiltrate the subcutis and lymphovascular surroundings (Figure 5).^16-19 Cells have scant eosinophilic cytoplasm and may have fine granular chromatin. Numerous mitotic figures and apoptotic cells also are present. On immunohistochemistry, these cells will stain positive for cytokeratin AE1/AE3, anticytokeratin (CAM 5.2), CK20, and CD56. Due to their neuroendocrine derivation, they also are commonly synaptophysin, neuron-specific enolase, and chromogranin A positive. Notably, MCC will stain negative for leukocyte common antigen, CD20, CD3, CD34, and thyroid transcription factor 1 (TTF-1).^16,17

Primary cutaneous γδ T-cell lymphoma can be difficult to diagnose and requires urgent treatment. Clinicians and dermatopathologists need to work together to establish the diagnosis. There is a high mortality rate associated with PCGDTL, making prompt recognition and timely treatment critical. Acknowledgments—Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

 

Acknowledgments
Thank you to our colleagues with the Penn State Health Hematology/Oncology Department (Hershey, Pennsylvania) for comanagement of this patient.

The Diagnosis: Erythropoietic Protoporphyria 

Erythropoietic protoporphyria (EPP) is an autosomal-recessive photodermatosis that results from loss of activity of ferrochelatase, the last enzyme in the heme biosynthetic pathway.¹ Erythropoietic protoporphyria normally involves sun-exposed areas of the body. Skin that is exposed to sunlight develops intense burning and stinging pain followed by erythema, edema, crusting, and petechiae that develops into waxy scarring over time. In contrast to other porphyrias, blistering generally is not seen.² Accurate diagnosis often can be delayed by a decade or more following symptom onset due to the prominence of subjective pain as the presenting sign.  

The histologic appearance of EPP differs depending on the chronicity of lesions. Biopsies of acute lesions show vacuolization of epidermal cells with intercellular edema, vacuolization and cytolysis of endothelial cells in superficial blood vessels, and focal red blood cell extravasation.^3,4 A largely neutrophilic inflammatory infiltrate can be present.⁵ Hyaline cuffing develops over time in and around vessels in the papillary and superficial reticular dermis with notable sparing of adnexal structures. The perivascular deposits are strongly periodic acid-Schiff (PAS) positive and diastase resistant (Figure 1). Direct immunofluorescence shows mainly IgG and some IgM, fibrinogen, and C3 outlining characteristic donut-shaped blood vessels in the papillary dermis.⁶ The prominent thickness of the perivascular hyaline material depositions and the absence of subepidermal blistering can help differentiate EPP from porphyria cutanea tarda (PCT) and pseudoporphyria.^6,7 When the deposition is extensive and involves the surrounding dermis, EPP can mimic colloid milium. Additional histologic differential diagnoses of EPP include other dermal depositional diseases such as lipoid proteinosis and amyloidosis.  

Lipoid proteinosis is an autosomal-recessive multisystem genodermatosis caused by mutations in extracellular matrix gene 1, ECM1. The first clinical sign can be a hoarse cry in infancy due to infiltration of vocal cords.³ Development of papulonodular lesions along the eyelids can result in a string-of-beads appearance called moniliform blepharosis, which is pathognomonic for lipoid proteinosis.⁶ With chronicity, the involved skin can become yellow, waxy, and thickened, particularly in the flexures or areas of trauma. Histologically, the dermis in lipoid proteinosis becomes diffusely thickened due to deposition of PAS-positive eosinophilic hyaline material that stains weakly with Congo red and thioflavin T.⁶ Early lesions demonstrate pale pink, hyalinelike thickening of the papillary dermal capillaries. Chronic lesions reveal an acanthotic epidermis, occasional papillomatosis with overlying hyperkeratosis, and a thickened dermis where diffuse thick bundles of pink hyaline deposits are oriented perpendicularly to the dermoepidermal junction.^1,6 Lipoid proteinosis can be differentiated from EPP by the involvement of adnexal structures such as hair follicles, sebaceous glands, and arrector pili muscles (Figure 2), as opposed to EPP where adnexal structures are spared.¹ Additionally, depositions in lipoid proteinosis are centered around both superficial and deep vessels with an onion skin-like pattern, while EPP involves mainly superficial vessels with more mild and focal hyalinization.

 

Juvenile colloid milium (JCM) is a rare condition that presents before puberty with discrete, yellow-brown, translucent papules predominantly located on the cheeks and nose and around the mouth. A gelatinous material can be expressed after puncturing a lesion.⁶ Gingival deposits and ligneous conjunctivitis also can be present. On histopathology, JCM shows degeneration of epidermal keratinocytes that form colloid bodies within the superficial dermis following apoptosis.⁶ Hematoxylin and eosin staining shows amorphous, fissured, pale pink deposits completely filling and expanding the superficial to mid dermis with clefting and no inflammation (Figure 3). Spindle-shaped fibroblasts may be seen within the lines of colloid fissuring and dispersed throughout the deposits.¹ Histologically, JCM can be differentiated from EPP because deposits in EPP are distributed around and within superficial blood vessel walls, causing prominent vascular thickening not seen in JCM.⁶ The adult variant of colloid milium also can be distinguished from EPP by the presence of solar elastosis, which is absent in EPP due to a history of sun avoidance.^3,7  

Lichen amyloidosis presents with highly pruritic, red-brown, hyperkeratotic papules that commonly are found on the anterior lower legs and extensor forearms.¹ The calves, ankles, dorsal aspects of the feet, thighs, and trunk also may be affected. Excoriations, lichenification, and nodular prurigo-like lesions due to chronic scratching can be present.⁶ Lichen amyloidosis is characterized by large, pink, amorphous deposits in the papillary dermis with epidermal acanthosis, hypergranulosis, and hyperkeratosis (Figure 4).⁶ Perivascular deposits are not a feature of primary cutaneous localized amyloid lesions.⁶ The diagnosis can be confirmed with Congo red staining under polarized light, which classically demonstrates apple green birefringence.¹ For cases of amyloid that are not detected by Congo red or are not clear-cut, direct immunofluorescence and immunohistochemistry can be used as adjuncts for diagnosis. Amyloid deposits fluoresce positively for immunoglobulins or complements, particularly IgM and C3,⁸ and immunohistochemistry confirms the presence of keratin epitopes in deposits.⁹  

Porphyria cutanea tarda can appear histologically similar to EPP. Caterpillar bodies, or linearly arranged eosinophilic PAS-positive globules in the epidermis overlying subepidermal bullae, are a diagnostic histopathologic finding in both PCT and EPP but are seen in less than half of both cases.^7,10 Compared to EPP, the perivascular deposits in PCT typically are less pronounced and limited to the vessel wall with smaller hyaline cuffs (Figure 5).⁷ Additionally, solar elastosis can be seen in PCT lesions but not in EPP, as patients with PCT tend to be older and have increased cumulative sun damage.  

The Diagnosis: Erythropoietic Protoporphyria 

Erythropoietic protoporphyria (EPP) is an autosomal-recessive photodermatosis that results from loss of activity of ferrochelatase, the last enzyme in the heme biosynthetic pathway.¹ Erythropoietic protoporphyria normally involves sun-exposed areas of the body. Skin that is exposed to sunlight develops intense burning and stinging pain followed by erythema, edema, crusting, and petechiae that develops into waxy scarring over time. In contrast to other porphyrias, blistering generally is not seen.² Accurate diagnosis often can be delayed by a decade or more following symptom onset due to the prominence of subjective pain as the presenting sign.  

The histologic appearance of EPP differs depending on the chronicity of lesions. Biopsies of acute lesions show vacuolization of epidermal cells with intercellular edema, vacuolization and cytolysis of endothelial cells in superficial blood vessels, and focal red blood cell extravasation.^3,4 A largely neutrophilic inflammatory infiltrate can be present.⁵ Hyaline cuffing develops over time in and around vessels in the papillary and superficial reticular dermis with notable sparing of adnexal structures. The perivascular deposits are strongly periodic acid-Schiff (PAS) positive and diastase resistant (Figure 1). Direct immunofluorescence shows mainly IgG and some IgM, fibrinogen, and C3 outlining characteristic donut-shaped blood vessels in the papillary dermis.⁶ The prominent thickness of the perivascular hyaline material depositions and the absence of subepidermal blistering can help differentiate EPP from porphyria cutanea tarda (PCT) and pseudoporphyria.^6,7 When the deposition is extensive and involves the surrounding dermis, EPP can mimic colloid milium. Additional histologic differential diagnoses of EPP include other dermal depositional diseases such as lipoid proteinosis and amyloidosis.  

Lipoid proteinosis is an autosomal-recessive multisystem genodermatosis caused by mutations in extracellular matrix gene 1, ECM1. The first clinical sign can be a hoarse cry in infancy due to infiltration of vocal cords.³ Development of papulonodular lesions along the eyelids can result in a string-of-beads appearance called moniliform blepharosis, which is pathognomonic for lipoid proteinosis.⁶ With chronicity, the involved skin can become yellow, waxy, and thickened, particularly in the flexures or areas of trauma. Histologically, the dermis in lipoid proteinosis becomes diffusely thickened due to deposition of PAS-positive eosinophilic hyaline material that stains weakly with Congo red and thioflavin T.⁶ Early lesions demonstrate pale pink, hyalinelike thickening of the papillary dermal capillaries. Chronic lesions reveal an acanthotic epidermis, occasional papillomatosis with overlying hyperkeratosis, and a thickened dermis where diffuse thick bundles of pink hyaline deposits are oriented perpendicularly to the dermoepidermal junction.^1,6 Lipoid proteinosis can be differentiated from EPP by the involvement of adnexal structures such as hair follicles, sebaceous glands, and arrector pili muscles (Figure 2), as opposed to EPP where adnexal structures are spared.¹ Additionally, depositions in lipoid proteinosis are centered around both superficial and deep vessels with an onion skin-like pattern, while EPP involves mainly superficial vessels with more mild and focal hyalinization.

 

Juvenile colloid milium (JCM) is a rare condition that presents before puberty with discrete, yellow-brown, translucent papules predominantly located on the cheeks and nose and around the mouth. A gelatinous material can be expressed after puncturing a lesion.⁶ Gingival deposits and ligneous conjunctivitis also can be present. On histopathology, JCM shows degeneration of epidermal keratinocytes that form colloid bodies within the superficial dermis following apoptosis.⁶ Hematoxylin and eosin staining shows amorphous, fissured, pale pink deposits completely filling and expanding the superficial to mid dermis with clefting and no inflammation (Figure 3). Spindle-shaped fibroblasts may be seen within the lines of colloid fissuring and dispersed throughout the deposits.¹ Histologically, JCM can be differentiated from EPP because deposits in EPP are distributed around and within superficial blood vessel walls, causing prominent vascular thickening not seen in JCM.⁶ The adult variant of colloid milium also can be distinguished from EPP by the presence of solar elastosis, which is absent in EPP due to a history of sun avoidance.^3,7  

Lichen amyloidosis presents with highly pruritic, red-brown, hyperkeratotic papules that commonly are found on the anterior lower legs and extensor forearms.¹ The calves, ankles, dorsal aspects of the feet, thighs, and trunk also may be affected. Excoriations, lichenification, and nodular prurigo-like lesions due to chronic scratching can be present.⁶ Lichen amyloidosis is characterized by large, pink, amorphous deposits in the papillary dermis with epidermal acanthosis, hypergranulosis, and hyperkeratosis (Figure 4).⁶ Perivascular deposits are not a feature of primary cutaneous localized amyloid lesions.⁶ The diagnosis can be confirmed with Congo red staining under polarized light, which classically demonstrates apple green birefringence.¹ For cases of amyloid that are not detected by Congo red or are not clear-cut, direct immunofluorescence and immunohistochemistry can be used as adjuncts for diagnosis. Amyloid deposits fluoresce positively for immunoglobulins or complements, particularly IgM and C3,⁸ and immunohistochemistry confirms the presence of keratin epitopes in deposits.⁹  

Porphyria cutanea tarda can appear histologically similar to EPP. Caterpillar bodies, or linearly arranged eosinophilic PAS-positive globules in the epidermis overlying subepidermal bullae, are a diagnostic histopathologic finding in both PCT and EPP but are seen in less than half of both cases.^7,10 Compared to EPP, the perivascular deposits in PCT typically are less pronounced and limited to the vessel wall with smaller hyaline cuffs (Figure 5).⁷ Additionally, solar elastosis can be seen in PCT lesions but not in EPP, as patients with PCT tend to be older and have increased cumulative sun damage.  

The Diagnosis: Erythropoietic Protoporphyria 

Erythropoietic protoporphyria (EPP) is an autosomal-recessive photodermatosis that results from loss of activity of ferrochelatase, the last enzyme in the heme biosynthetic pathway.¹ Erythropoietic protoporphyria normally involves sun-exposed areas of the body. Skin that is exposed to sunlight develops intense burning and stinging pain followed by erythema, edema, crusting, and petechiae that develops into waxy scarring over time. In contrast to other porphyrias, blistering generally is not seen.² Accurate diagnosis often can be delayed by a decade or more following symptom onset due to the prominence of subjective pain as the presenting sign.  

The histologic appearance of EPP differs depending on the chronicity of lesions. Biopsies of acute lesions show vacuolization of epidermal cells with intercellular edema, vacuolization and cytolysis of endothelial cells in superficial blood vessels, and focal red blood cell extravasation.^3,4 A largely neutrophilic inflammatory infiltrate can be present.⁵ Hyaline cuffing develops over time in and around vessels in the papillary and superficial reticular dermis with notable sparing of adnexal structures. The perivascular deposits are strongly periodic acid-Schiff (PAS) positive and diastase resistant (Figure 1). Direct immunofluorescence shows mainly IgG and some IgM, fibrinogen, and C3 outlining characteristic donut-shaped blood vessels in the papillary dermis.⁶ The prominent thickness of the perivascular hyaline material depositions and the absence of subepidermal blistering can help differentiate EPP from porphyria cutanea tarda (PCT) and pseudoporphyria.^6,7 When the deposition is extensive and involves the surrounding dermis, EPP can mimic colloid milium. Additional histologic differential diagnoses of EPP include other dermal depositional diseases such as lipoid proteinosis and amyloidosis.  

Lipoid proteinosis is an autosomal-recessive multisystem genodermatosis caused by mutations in extracellular matrix gene 1, ECM1. The first clinical sign can be a hoarse cry in infancy due to infiltration of vocal cords.³ Development of papulonodular lesions along the eyelids can result in a string-of-beads appearance called moniliform blepharosis, which is pathognomonic for lipoid proteinosis.⁶ With chronicity, the involved skin can become yellow, waxy, and thickened, particularly in the flexures or areas of trauma. Histologically, the dermis in lipoid proteinosis becomes diffusely thickened due to deposition of PAS-positive eosinophilic hyaline material that stains weakly with Congo red and thioflavin T.⁶ Early lesions demonstrate pale pink, hyalinelike thickening of the papillary dermal capillaries. Chronic lesions reveal an acanthotic epidermis, occasional papillomatosis with overlying hyperkeratosis, and a thickened dermis where diffuse thick bundles of pink hyaline deposits are oriented perpendicularly to the dermoepidermal junction.^1,6 Lipoid proteinosis can be differentiated from EPP by the involvement of adnexal structures such as hair follicles, sebaceous glands, and arrector pili muscles (Figure 2), as opposed to EPP where adnexal structures are spared.¹ Additionally, depositions in lipoid proteinosis are centered around both superficial and deep vessels with an onion skin-like pattern, while EPP involves mainly superficial vessels with more mild and focal hyalinization.

 

Juvenile colloid milium (JCM) is a rare condition that presents before puberty with discrete, yellow-brown, translucent papules predominantly located on the cheeks and nose and around the mouth. A gelatinous material can be expressed after puncturing a lesion.⁶ Gingival deposits and ligneous conjunctivitis also can be present. On histopathology, JCM shows degeneration of epidermal keratinocytes that form colloid bodies within the superficial dermis following apoptosis.⁶ Hematoxylin and eosin staining shows amorphous, fissured, pale pink deposits completely filling and expanding the superficial to mid dermis with clefting and no inflammation (Figure 3). Spindle-shaped fibroblasts may be seen within the lines of colloid fissuring and dispersed throughout the deposits.¹ Histologically, JCM can be differentiated from EPP because deposits in EPP are distributed around and within superficial blood vessel walls, causing prominent vascular thickening not seen in JCM.⁶ The adult variant of colloid milium also can be distinguished from EPP by the presence of solar elastosis, which is absent in EPP due to a history of sun avoidance.^3,7  

Lichen amyloidosis presents with highly pruritic, red-brown, hyperkeratotic papules that commonly are found on the anterior lower legs and extensor forearms.¹ The calves, ankles, dorsal aspects of the feet, thighs, and trunk also may be affected. Excoriations, lichenification, and nodular prurigo-like lesions due to chronic scratching can be present.⁶ Lichen amyloidosis is characterized by large, pink, amorphous deposits in the papillary dermis with epidermal acanthosis, hypergranulosis, and hyperkeratosis (Figure 4).⁶ Perivascular deposits are not a feature of primary cutaneous localized amyloid lesions.⁶ The diagnosis can be confirmed with Congo red staining under polarized light, which classically demonstrates apple green birefringence.¹ For cases of amyloid that are not detected by Congo red or are not clear-cut, direct immunofluorescence and immunohistochemistry can be used as adjuncts for diagnosis. Amyloid deposits fluoresce positively for immunoglobulins or complements, particularly IgM and C3,⁸ and immunohistochemistry confirms the presence of keratin epitopes in deposits.⁹  

Porphyria cutanea tarda can appear histologically similar to EPP. Caterpillar bodies, or linearly arranged eosinophilic PAS-positive globules in the epidermis overlying subepidermal bullae, are a diagnostic histopathologic finding in both PCT and EPP but are seen in less than half of both cases.^7,10 Compared to EPP, the perivascular deposits in PCT typically are less pronounced and limited to the vessel wall with smaller hyaline cuffs (Figure 5).⁷ Additionally, solar elastosis can be seen in PCT lesions but not in EPP, as patients with PCT tend to be older and have increased cumulative sun damage.  

The Diagnosis: Scleredema Diabeticorum  

Histologically, scleredema is characterized by mucin deposition between collagen bundles in the deep dermis. Clinically, it is characterized by a progressive indurated plaque with associated stiffness of the involved area. It most commonly presents on the posterior aspect of the neck, though it can extend to involve the shoulders and upper torso.¹ Scleredema is divided into 3 subtypes based on clinical associations. Type 1 often is preceded by an infection, most commonly group A Streptococcus. This type occurs acutely and often resolves completely over a few months.² Type 2, which has progressive onset, is associated with monoclonal gammopathy.³ Type 3 is the most common type and is associated with diabetes mellitus. A study of 484 patients with type 2 diabetes mellitus demonstrated a prevalence of 2.5%.⁴ Although the exact pathogenesis has not been defined, it is hypothesized that irreversible glycosylation of collagen and alterations in collagenase activity may lead to accumulation of collagen and mucin in the dermis.⁵ Similar to type 2, type 3 scleredema appears subtly, progresses slowly, and tends to be chronic.^1,6 Scleredema is characterized by marked dermal thickening and enlarged collagen bundles separated by mucin deposition (Figure 1). Fibroblast proliferation is characteristically absent.¹ 

Clinically, tumid lupus erythematosus presents with erythematous edematous plaques on sun-exposed areas.⁷ Pretibial myxedema (PM) classically is associated with Graves disease; however, it can present in association with other types of thyroid dysfunction. Classically, PM presents on the pretibial regions as well-demarcated erythematous or hyperpigmented plaques.⁸ Similar to scleredema, histologic examination of tumid lupus erythematosus and PM reveals mucin deposition. Tumid lupus erythematosus also may demonstrate periadnexal and perivascular lymphocytic inflammation (Figure 2).⁷ The collagen bundles present in PM often are thin in comparison to scleredema (Figure 3).⁸ 

Scleroderma also presents with skin induration, erythema, and stiffening. However, unlike scleredema, scleroderma commonly involves the fingers, toes, and face. It presents with symptoms of Raynaud phenomenon, painful digital nonpitting edema, perioral skin tightening, mucocutaneous telangiectasia, and calcinosis cutis. Scleroderma also can involve organs such as the lungs, heart, kidneys, and gastrointestinal tract.⁹ Histologically, scleroderma is characterized by a compact dermis with closely packed collagen bundles. Other features of scleroderma can include perivascular mononuclear inflammatory cell infiltration, progressive atrophy of intradermal and perieccrine fat, and fibrosis (Figure 4).¹⁰ 

Scleromyxedema, also called papular mucinosis, is primary dermal mucinosis that often presents with waxy, dome-shaped papules that may coalesce into plaques. Similar to scleredema, scleromyxedema shows increased mucin deposition. However, scleromyxedema commonly is associated with fibroblast proliferation, which is characteristically absent in scleredema (Figure 5).¹¹

The Diagnosis: Scleredema Diabeticorum  

Histologically, scleredema is characterized by mucin deposition between collagen bundles in the deep dermis. Clinically, it is characterized by a progressive indurated plaque with associated stiffness of the involved area. It most commonly presents on the posterior aspect of the neck, though it can extend to involve the shoulders and upper torso.¹ Scleredema is divided into 3 subtypes based on clinical associations. Type 1 often is preceded by an infection, most commonly group A Streptococcus. This type occurs acutely and often resolves completely over a few months.² Type 2, which has progressive onset, is associated with monoclonal gammopathy.³ Type 3 is the most common type and is associated with diabetes mellitus. A study of 484 patients with type 2 diabetes mellitus demonstrated a prevalence of 2.5%.⁴ Although the exact pathogenesis has not been defined, it is hypothesized that irreversible glycosylation of collagen and alterations in collagenase activity may lead to accumulation of collagen and mucin in the dermis.⁵ Similar to type 2, type 3 scleredema appears subtly, progresses slowly, and tends to be chronic.^1,6 Scleredema is characterized by marked dermal thickening and enlarged collagen bundles separated by mucin deposition (Figure 1). Fibroblast proliferation is characteristically absent.¹ 

Clinically, tumid lupus erythematosus presents with erythematous edematous plaques on sun-exposed areas.⁷ Pretibial myxedema (PM) classically is associated with Graves disease; however, it can present in association with other types of thyroid dysfunction. Classically, PM presents on the pretibial regions as well-demarcated erythematous or hyperpigmented plaques.⁸ Similar to scleredema, histologic examination of tumid lupus erythematosus and PM reveals mucin deposition. Tumid lupus erythematosus also may demonstrate periadnexal and perivascular lymphocytic inflammation (Figure 2).⁷ The collagen bundles present in PM often are thin in comparison to scleredema (Figure 3).⁸ 

Scleroderma also presents with skin induration, erythema, and stiffening. However, unlike scleredema, scleroderma commonly involves the fingers, toes, and face. It presents with symptoms of Raynaud phenomenon, painful digital nonpitting edema, perioral skin tightening, mucocutaneous telangiectasia, and calcinosis cutis. Scleroderma also can involve organs such as the lungs, heart, kidneys, and gastrointestinal tract.⁹ Histologically, scleroderma is characterized by a compact dermis with closely packed collagen bundles. Other features of scleroderma can include perivascular mononuclear inflammatory cell infiltration, progressive atrophy of intradermal and perieccrine fat, and fibrosis (Figure 4).¹⁰ 

Scleromyxedema, also called papular mucinosis, is primary dermal mucinosis that often presents with waxy, dome-shaped papules that may coalesce into plaques. Similar to scleredema, scleromyxedema shows increased mucin deposition. However, scleromyxedema commonly is associated with fibroblast proliferation, which is characteristically absent in scleredema (Figure 5).¹¹

The Diagnosis: Scleredema Diabeticorum  

Histologically, scleredema is characterized by mucin deposition between collagen bundles in the deep dermis. Clinically, it is characterized by a progressive indurated plaque with associated stiffness of the involved area. It most commonly presents on the posterior aspect of the neck, though it can extend to involve the shoulders and upper torso.¹ Scleredema is divided into 3 subtypes based on clinical associations. Type 1 often is preceded by an infection, most commonly group A Streptococcus. This type occurs acutely and often resolves completely over a few months.² Type 2, which has progressive onset, is associated with monoclonal gammopathy.³ Type 3 is the most common type and is associated with diabetes mellitus. A study of 484 patients with type 2 diabetes mellitus demonstrated a prevalence of 2.5%.⁴ Although the exact pathogenesis has not been defined, it is hypothesized that irreversible glycosylation of collagen and alterations in collagenase activity may lead to accumulation of collagen and mucin in the dermis.⁵ Similar to type 2, type 3 scleredema appears subtly, progresses slowly, and tends to be chronic.^1,6 Scleredema is characterized by marked dermal thickening and enlarged collagen bundles separated by mucin deposition (Figure 1). Fibroblast proliferation is characteristically absent.¹ 

Clinically, tumid lupus erythematosus presents with erythematous edematous plaques on sun-exposed areas.⁷ Pretibial myxedema (PM) classically is associated with Graves disease; however, it can present in association with other types of thyroid dysfunction. Classically, PM presents on the pretibial regions as well-demarcated erythematous or hyperpigmented plaques.⁸ Similar to scleredema, histologic examination of tumid lupus erythematosus and PM reveals mucin deposition. Tumid lupus erythematosus also may demonstrate periadnexal and perivascular lymphocytic inflammation (Figure 2).⁷ The collagen bundles present in PM often are thin in comparison to scleredema (Figure 3).⁸ 

Scleroderma also presents with skin induration, erythema, and stiffening. However, unlike scleredema, scleroderma commonly involves the fingers, toes, and face. It presents with symptoms of Raynaud phenomenon, painful digital nonpitting edema, perioral skin tightening, mucocutaneous telangiectasia, and calcinosis cutis. Scleroderma also can involve organs such as the lungs, heart, kidneys, and gastrointestinal tract.⁹ Histologically, scleroderma is characterized by a compact dermis with closely packed collagen bundles. Other features of scleroderma can include perivascular mononuclear inflammatory cell infiltration, progressive atrophy of intradermal and perieccrine fat, and fibrosis (Figure 4).¹⁰ 

Scleromyxedema, also called papular mucinosis, is primary dermal mucinosis that often presents with waxy, dome-shaped papules that may coalesce into plaques. Similar to scleredema, scleromyxedema shows increased mucin deposition. However, scleromyxedema commonly is associated with fibroblast proliferation, which is characteristically absent in scleredema (Figure 5).¹¹

To the Editor:

A 46-year-old overweight woman presented with a rash in the axillae of 2 months’ duration. She did not report any additional symptoms such as pruritus or pain. She reported changing her deodorant recently from Secret Original to Secret Clinical Strength (both Procter & Gamble). Her medical history was remarkable for asthma and gastroesophageal reflux disease. Clinical examination revealed erythematous-brown, stuccolike, hyperkeratotic papules coalescing into plaques in recently shaved axillae, affecting the left axilla more than the right axilla (Figure 1). The clinical differential diagnosis included granular parakeratosis, intertrigo, Hailey-Hailey disease, Darier disease, pemphigus vegetans, confluent and reticulated papillomatosis, acanthosis nigricans, seborrheic keratoses, and irritant or allergic contact dermatitis. A punch biopsy revealed a marked compact parakeratotic horn with retention of keratohyalin granules (Figure 2). The subjacent epidermis showed some acanthosis and spongiosis with mild chronic inflammation of the dermal rim. Based on histopathology, granular parakeratosis was diagnosed.

At a subsequent visit 2 weeks later, we prescribed glycolic acid lotion 10% applied to the axillae twice daily, plus tretinoin gel 0.05% applied to the axillae each evening. She reported clearing after 1 week of therapy. She also had changed her deodorant from Secret Clinical Strength back to the usual Secret Original. The patient discontinued topical treatment after clearing of the lesions. Three weeks later, clinical examination revealed postinflammatory hyperpigmentation in the axillae, and the prior lesions had resolved (Figure 3).

Granular parakeratosis is an unusual condition most commonly presenting in middle-aged women in the axillae, with a clinical presentation of erythematous to brownish hyperkeratotic papules coalescing into plaques. Although few cases have been reported, granular parakeratosis likely is more common than has been reported. There have been reports involving the scalp, cheeks, abdomen, thighs, and other intertriginous areas including inguinal folds and the submammary region.^1-4 There also is an infantile form related to diapers and zinc oxide paste.⁵ Although uncommon, granular parakeratosis can occur as a single papule or plaque and is termed granular parakeratotic acanthoma.⁶ Lesions may persist for months, spontaneously resolve and recur, and occasionally evolve into fissures and erosions due to irritation. Pruritus is a common concern. Histology of granular parakeratosis reveals hyperkeratosis with eosinophilic staining, compact parakeratosis with retention of basophilic keratohyalin granules, and vascular proliferation and ectasia.⁵

The cause is unknown but possibly related to irritation from rubbing, occlusion, sweating, or deodorants.^5,7 Cases indicate a link to obesity. Hypotheses as to the etiology include the disruption of cornification. Normally, filaggrin maintains the keratohyaline granules in the stratum corneum during cornification. Therefore, the retention of keratohyaline granules in granular parakeratosis may be due to a defect in processing profilaggrin to filaggrin, which has been proposed based on ultrastructural and immunohistochemical studies.⁸

The differential diagnosis includes granular parakeratosis, intertrigo (caused by seborrheic dermatitis, candidiasis, inverse psoriasis, or erythrasma), Hailey-Hailey disease, Darier disease, pemphigus vegetans, confluent and reticulated papillomatosis, and irritant or allergic contact dermatitis. The papules may resemble seborrheic keratoses, while the plaques can be mistaken for acanthosis nigricans.

Therapeutic success has been reported with topical corticosteroids, vitamin D analogues, topical or oral retinoids, ammonium lactate, calcineurin inhibitors, topical or oral antifungals, cryotherapy, and botulinum toxin injections.^3,9-11 In addition, parakeratosis has decreased in biopsies from psoriatic patients after acitretin, methotrexate, and phototherapy, which may be alternative treatments for unusually difficult or recalcitrant cases of granular parakeratosis. To minimize side effects and resolve the papules quickly, we combined 2 synergistic agents—glycolic acid and tretinoin—each with different mechanisms of action, and we observed excellent clinical response.

Granular parakeratosis is possibly related to a combination of topical products that potentiate irritation, rubbing, and occlusion of sweat. Multiple treatment modalities likely contribute to clearing, the most important being removal of any triggering topical products. Our patient’s change in deodorant may have been the inciting factor for the disease. Withdrawal of the Secret Clinical Strength deodorant prompted clearing, though topical retinoid and glycolic acid acted as facilitating therapies for timely results. A thorough history, as highlighted by this case, may help pinpoint etiologic factors. By identifying a seemingly innocuous change in hygienic routine, we were able to minimize the need for ongoing therapy.

To the Editor:

A 46-year-old overweight woman presented with a rash in the axillae of 2 months’ duration. She did not report any additional symptoms such as pruritus or pain. She reported changing her deodorant recently from Secret Original to Secret Clinical Strength (both Procter & Gamble). Her medical history was remarkable for asthma and gastroesophageal reflux disease. Clinical examination revealed erythematous-brown, stuccolike, hyperkeratotic papules coalescing into plaques in recently shaved axillae, affecting the left axilla more than the right axilla (Figure 1). The clinical differential diagnosis included granular parakeratosis, intertrigo, Hailey-Hailey disease, Darier disease, pemphigus vegetans, confluent and reticulated papillomatosis, acanthosis nigricans, seborrheic keratoses, and irritant or allergic contact dermatitis. A punch biopsy revealed a marked compact parakeratotic horn with retention of keratohyalin granules (Figure 2). The subjacent epidermis showed some acanthosis and spongiosis with mild chronic inflammation of the dermal rim. Based on histopathology, granular parakeratosis was diagnosed.

At a subsequent visit 2 weeks later, we prescribed glycolic acid lotion 10% applied to the axillae twice daily, plus tretinoin gel 0.05% applied to the axillae each evening. She reported clearing after 1 week of therapy. She also had changed her deodorant from Secret Clinical Strength back to the usual Secret Original. The patient discontinued topical treatment after clearing of the lesions. Three weeks later, clinical examination revealed postinflammatory hyperpigmentation in the axillae, and the prior lesions had resolved (Figure 3).

Granular parakeratosis is an unusual condition most commonly presenting in middle-aged women in the axillae, with a clinical presentation of erythematous to brownish hyperkeratotic papules coalescing into plaques. Although few cases have been reported, granular parakeratosis likely is more common than has been reported. There have been reports involving the scalp, cheeks, abdomen, thighs, and other intertriginous areas including inguinal folds and the submammary region.^1-4 There also is an infantile form related to diapers and zinc oxide paste.⁵ Although uncommon, granular parakeratosis can occur as a single papule or plaque and is termed granular parakeratotic acanthoma.⁶ Lesions may persist for months, spontaneously resolve and recur, and occasionally evolve into fissures and erosions due to irritation. Pruritus is a common concern. Histology of granular parakeratosis reveals hyperkeratosis with eosinophilic staining, compact parakeratosis with retention of basophilic keratohyalin granules, and vascular proliferation and ectasia.⁵

The cause is unknown but possibly related to irritation from rubbing, occlusion, sweating, or deodorants.^5,7 Cases indicate a link to obesity. Hypotheses as to the etiology include the disruption of cornification. Normally, filaggrin maintains the keratohyaline granules in the stratum corneum during cornification. Therefore, the retention of keratohyaline granules in granular parakeratosis may be due to a defect in processing profilaggrin to filaggrin, which has been proposed based on ultrastructural and immunohistochemical studies.⁸

The differential diagnosis includes granular parakeratosis, intertrigo (caused by seborrheic dermatitis, candidiasis, inverse psoriasis, or erythrasma), Hailey-Hailey disease, Darier disease, pemphigus vegetans, confluent and reticulated papillomatosis, and irritant or allergic contact dermatitis. The papules may resemble seborrheic keratoses, while the plaques can be mistaken for acanthosis nigricans.

Therapeutic success has been reported with topical corticosteroids, vitamin D analogues, topical or oral retinoids, ammonium lactate, calcineurin inhibitors, topical or oral antifungals, cryotherapy, and botulinum toxin injections.^3,9-11 In addition, parakeratosis has decreased in biopsies from psoriatic patients after acitretin, methotrexate, and phototherapy, which may be alternative treatments for unusually difficult or recalcitrant cases of granular parakeratosis. To minimize side effects and resolve the papules quickly, we combined 2 synergistic agents—glycolic acid and tretinoin—each with different mechanisms of action, and we observed excellent clinical response.

Granular parakeratosis is possibly related to a combination of topical products that potentiate irritation, rubbing, and occlusion of sweat. Multiple treatment modalities likely contribute to clearing, the most important being removal of any triggering topical products. Our patient’s change in deodorant may have been the inciting factor for the disease. Withdrawal of the Secret Clinical Strength deodorant prompted clearing, though topical retinoid and glycolic acid acted as facilitating therapies for timely results. A thorough history, as highlighted by this case, may help pinpoint etiologic factors. By identifying a seemingly innocuous change in hygienic routine, we were able to minimize the need for ongoing therapy.

To the Editor:

A 46-year-old overweight woman presented with a rash in the axillae of 2 months’ duration. She did not report any additional symptoms such as pruritus or pain. She reported changing her deodorant recently from Secret Original to Secret Clinical Strength (both Procter & Gamble). Her medical history was remarkable for asthma and gastroesophageal reflux disease. Clinical examination revealed erythematous-brown, stuccolike, hyperkeratotic papules coalescing into plaques in recently shaved axillae, affecting the left axilla more than the right axilla (Figure 1). The clinical differential diagnosis included granular parakeratosis, intertrigo, Hailey-Hailey disease, Darier disease, pemphigus vegetans, confluent and reticulated papillomatosis, acanthosis nigricans, seborrheic keratoses, and irritant or allergic contact dermatitis. A punch biopsy revealed a marked compact parakeratotic horn with retention of keratohyalin granules (Figure 2). The subjacent epidermis showed some acanthosis and spongiosis with mild chronic inflammation of the dermal rim. Based on histopathology, granular parakeratosis was diagnosed.

At a subsequent visit 2 weeks later, we prescribed glycolic acid lotion 10% applied to the axillae twice daily, plus tretinoin gel 0.05% applied to the axillae each evening. She reported clearing after 1 week of therapy. She also had changed her deodorant from Secret Clinical Strength back to the usual Secret Original. The patient discontinued topical treatment after clearing of the lesions. Three weeks later, clinical examination revealed postinflammatory hyperpigmentation in the axillae, and the prior lesions had resolved (Figure 3).

Granular parakeratosis is an unusual condition most commonly presenting in middle-aged women in the axillae, with a clinical presentation of erythematous to brownish hyperkeratotic papules coalescing into plaques. Although few cases have been reported, granular parakeratosis likely is more common than has been reported. There have been reports involving the scalp, cheeks, abdomen, thighs, and other intertriginous areas including inguinal folds and the submammary region.^1-4 There also is an infantile form related to diapers and zinc oxide paste.⁵ Although uncommon, granular parakeratosis can occur as a single papule or plaque and is termed granular parakeratotic acanthoma.⁶ Lesions may persist for months, spontaneously resolve and recur, and occasionally evolve into fissures and erosions due to irritation. Pruritus is a common concern. Histology of granular parakeratosis reveals hyperkeratosis with eosinophilic staining, compact parakeratosis with retention of basophilic keratohyalin granules, and vascular proliferation and ectasia.⁵

The cause is unknown but possibly related to irritation from rubbing, occlusion, sweating, or deodorants.^5,7 Cases indicate a link to obesity. Hypotheses as to the etiology include the disruption of cornification. Normally, filaggrin maintains the keratohyaline granules in the stratum corneum during cornification. Therefore, the retention of keratohyaline granules in granular parakeratosis may be due to a defect in processing profilaggrin to filaggrin, which has been proposed based on ultrastructural and immunohistochemical studies.⁸

The differential diagnosis includes granular parakeratosis, intertrigo (caused by seborrheic dermatitis, candidiasis, inverse psoriasis, or erythrasma), Hailey-Hailey disease, Darier disease, pemphigus vegetans, confluent and reticulated papillomatosis, and irritant or allergic contact dermatitis. The papules may resemble seborrheic keratoses, while the plaques can be mistaken for acanthosis nigricans.

Therapeutic success has been reported with topical corticosteroids, vitamin D analogues, topical or oral retinoids, ammonium lactate, calcineurin inhibitors, topical or oral antifungals, cryotherapy, and botulinum toxin injections.^3,9-11 In addition, parakeratosis has decreased in biopsies from psoriatic patients after acitretin, methotrexate, and phototherapy, which may be alternative treatments for unusually difficult or recalcitrant cases of granular parakeratosis. To minimize side effects and resolve the papules quickly, we combined 2 synergistic agents—glycolic acid and tretinoin—each with different mechanisms of action, and we observed excellent clinical response.

Granular parakeratosis is possibly related to a combination of topical products that potentiate irritation, rubbing, and occlusion of sweat. Multiple treatment modalities likely contribute to clearing, the most important being removal of any triggering topical products. Our patient’s change in deodorant may have been the inciting factor for the disease. Withdrawal of the Secret Clinical Strength deodorant prompted clearing, though topical retinoid and glycolic acid acted as facilitating therapies for timely results. A thorough history, as highlighted by this case, may help pinpoint etiologic factors. By identifying a seemingly innocuous change in hygienic routine, we were able to minimize the need for ongoing therapy.

There are at least five dermatologic patterns in patients who are suspected or confirmed of having COVID-19, and the knowledge base continues to evolve, according to Christine Ko, MD.

“Things are very fluid,” Dr. Ko, professor of dermatology and pathology at Yale University, New Haven, Conn., said during the virtual annual meeting of the American Academy of Dermatology. “New studies are coming out daily. Due to the need for rapid dissemination, a lot of the studies are case reports, but there are some nice case series. Another caveat for the literature is that a lot of these cases were not necessarily confirmed with testing for SARS-CoV-2, but some were.”

Dr. Ko framed her remarks largely on a case collection survey of images and clinical data from 375 patients in Spain with suspected or confirmed COVID-19 that was published online April 29, 2020, in the British Journal of Dermatology (doi: 10.1111/bjd.19163). Cutaneous manifestations included early vesicular eruptions mainly on the trunk or limbs (9%), maculopapular (47%) to urticarial lesions (19%) mainly on the trunk, and acral areas of erythema sometimes with vesicles or erosion (perniosis-like) (19%) that seemed to be a later manifestation of COVID-19. Retiform purpura or necrosis (6%) was most concerning in terms of skin disease, with an associated with a mortality of 10%.

On histology, the early vesicular eruptions are typically marked by dyskeratotic keratinocytes, Dr. Ko said, while urticarial lesions are characterized by a mixed dermal infiltrate; maculopapular lesions were a broad category. “There are some case reports that show spongiotic dermatitis or parakeratosis with a lymphocytic infiltrate,” she said. “A caveat to keep in mind is that, although these patients may definitely have COVID-19 and be confirmed to have it by testing, hypersensitivity reactions may be due to the multiple medications they’re on.”

Patients can develop a spectrum of lesions that are suggestive of vascular damage or occlusion, Dr. Ko continued. Livedoid lesions may remain static and not eventuate into necrosis or purpura but will self-resolve. Purpuric lesions and acral gangrene have been described, and these lesions correspond to vascular occlusion on biopsy.

A later manifestation are the so-called “COVID toes” with a superficial and deep lymphocytic infiltrate, as published June 1, 2020, in JAAD Case Reports: (doi: 10.1016/j.jdcr.2020.04.011).

“There are patients in the literature that have slightly different pathology, with lymphocytic inflammation as well as occlusion of vessels,” Dr. Ko said. A paper published June 20, 2020, in the British Journal of Dermatology used immunohistochemical staining against the SARS-CoV-2 spike protein, and biopsies of “COVID toes” had positive staining of endothelial cells, supporting the notion that “COVID toes” are a direct manifestation of viral infection (doi: 10.1111/bjd.19327).

“There’s a lot that we still don’t know, and some patterns are going to be outliers,” Dr. Ko concluded. “[As for] determining which skin manifestations are directly from coronavirus infection within the skin, more study is needed and likely time will tell.” She reported having no financial disclosures relevant to her talk.

dbrunk@mdedge.com

There are at least five dermatologic patterns in patients who are suspected or confirmed of having COVID-19, and the knowledge base continues to evolve, according to Christine Ko, MD.

“Things are very fluid,” Dr. Ko, professor of dermatology and pathology at Yale University, New Haven, Conn., said during the virtual annual meeting of the American Academy of Dermatology. “New studies are coming out daily. Due to the need for rapid dissemination, a lot of the studies are case reports, but there are some nice case series. Another caveat for the literature is that a lot of these cases were not necessarily confirmed with testing for SARS-CoV-2, but some were.”

Dr. Ko framed her remarks largely on a case collection survey of images and clinical data from 375 patients in Spain with suspected or confirmed COVID-19 that was published online April 29, 2020, in the British Journal of Dermatology (doi: 10.1111/bjd.19163). Cutaneous manifestations included early vesicular eruptions mainly on the trunk or limbs (9%), maculopapular (47%) to urticarial lesions (19%) mainly on the trunk, and acral areas of erythema sometimes with vesicles or erosion (perniosis-like) (19%) that seemed to be a later manifestation of COVID-19. Retiform purpura or necrosis (6%) was most concerning in terms of skin disease, with an associated with a mortality of 10%.

On histology, the early vesicular eruptions are typically marked by dyskeratotic keratinocytes, Dr. Ko said, while urticarial lesions are characterized by a mixed dermal infiltrate; maculopapular lesions were a broad category. “There are some case reports that show spongiotic dermatitis or parakeratosis with a lymphocytic infiltrate,” she said. “A caveat to keep in mind is that, although these patients may definitely have COVID-19 and be confirmed to have it by testing, hypersensitivity reactions may be due to the multiple medications they’re on.”

Patients can develop a spectrum of lesions that are suggestive of vascular damage or occlusion, Dr. Ko continued. Livedoid lesions may remain static and not eventuate into necrosis or purpura but will self-resolve. Purpuric lesions and acral gangrene have been described, and these lesions correspond to vascular occlusion on biopsy.

A later manifestation are the so-called “COVID toes” with a superficial and deep lymphocytic infiltrate, as published June 1, 2020, in JAAD Case Reports: (doi: 10.1016/j.jdcr.2020.04.011).

“There are patients in the literature that have slightly different pathology, with lymphocytic inflammation as well as occlusion of vessels,” Dr. Ko said. A paper published June 20, 2020, in the British Journal of Dermatology used immunohistochemical staining against the SARS-CoV-2 spike protein, and biopsies of “COVID toes” had positive staining of endothelial cells, supporting the notion that “COVID toes” are a direct manifestation of viral infection (doi: 10.1111/bjd.19327).

“There’s a lot that we still don’t know, and some patterns are going to be outliers,” Dr. Ko concluded. “[As for] determining which skin manifestations are directly from coronavirus infection within the skin, more study is needed and likely time will tell.” She reported having no financial disclosures relevant to her talk.

dbrunk@mdedge.com

There are at least five dermatologic patterns in patients who are suspected or confirmed of having COVID-19, and the knowledge base continues to evolve, according to Christine Ko, MD.

“Things are very fluid,” Dr. Ko, professor of dermatology and pathology at Yale University, New Haven, Conn., said during the virtual annual meeting of the American Academy of Dermatology. “New studies are coming out daily. Due to the need for rapid dissemination, a lot of the studies are case reports, but there are some nice case series. Another caveat for the literature is that a lot of these cases were not necessarily confirmed with testing for SARS-CoV-2, but some were.”

Dr. Ko framed her remarks largely on a case collection survey of images and clinical data from 375 patients in Spain with suspected or confirmed COVID-19 that was published online April 29, 2020, in the British Journal of Dermatology (doi: 10.1111/bjd.19163). Cutaneous manifestations included early vesicular eruptions mainly on the trunk or limbs (9%), maculopapular (47%) to urticarial lesions (19%) mainly on the trunk, and acral areas of erythema sometimes with vesicles or erosion (perniosis-like) (19%) that seemed to be a later manifestation of COVID-19. Retiform purpura or necrosis (6%) was most concerning in terms of skin disease, with an associated with a mortality of 10%.

On histology, the early vesicular eruptions are typically marked by dyskeratotic keratinocytes, Dr. Ko said, while urticarial lesions are characterized by a mixed dermal infiltrate; maculopapular lesions were a broad category. “There are some case reports that show spongiotic dermatitis or parakeratosis with a lymphocytic infiltrate,” she said. “A caveat to keep in mind is that, although these patients may definitely have COVID-19 and be confirmed to have it by testing, hypersensitivity reactions may be due to the multiple medications they’re on.”

Patients can develop a spectrum of lesions that are suggestive of vascular damage or occlusion, Dr. Ko continued. Livedoid lesions may remain static and not eventuate into necrosis or purpura but will self-resolve. Purpuric lesions and acral gangrene have been described, and these lesions correspond to vascular occlusion on biopsy.

A later manifestation are the so-called “COVID toes” with a superficial and deep lymphocytic infiltrate, as published June 1, 2020, in JAAD Case Reports: (doi: 10.1016/j.jdcr.2020.04.011).

“There are patients in the literature that have slightly different pathology, with lymphocytic inflammation as well as occlusion of vessels,” Dr. Ko said. A paper published June 20, 2020, in the British Journal of Dermatology used immunohistochemical staining against the SARS-CoV-2 spike protein, and biopsies of “COVID toes” had positive staining of endothelial cells, supporting the notion that “COVID toes” are a direct manifestation of viral infection (doi: 10.1111/bjd.19327).

“There’s a lot that we still don’t know, and some patterns are going to be outliers,” Dr. Ko concluded. “[As for] determining which skin manifestations are directly from coronavirus infection within the skin, more study is needed and likely time will tell.” She reported having no financial disclosures relevant to her talk.

dbrunk@mdedge.com