Cutis

The practice of inpatient dermatology has a rich history rooted in specialized hospital wards that housed patients with chronic dermatoses. Because systemic agents were limited, the care of these patients required skilled nursing and a distinctive knowledge of the application of numerous topical agents, including washes, baths, powders, lotions, and pastes¹; however, with the evolving nature of health care in the last half a century, such dermatologic inpatient units are now rare, with only 2 units remaining in the United States, specifically at the Mayo Clinic in Minnesota and at the University of Miami.²

Although the shift away from a primary dermatologic admitting service is likely multifactorial, what is more sobering is that the majority of inpatients with dermatologic disorders are cared for by nondermatologists.² Although the dynamics for such a diminished presence are due to various personal and professional concerns, the essential outcome for patients hospitalized with a cutaneous concern—whether directly related to their hospitalization or iatrogenic in nature—is the potential for suboptimal care.³

Fortunately, the practice of inpatient dermatology currently is undergoing a renaissance. With this renewed interest in hospital-based dermatology, there is a growing body of evidence that demonstrates how the dermatology hospitalist has become a vital member of the inpatient team, adding value to the care of patients across all specialties.

To explore the impact of consultative dermatology services, there has been a push by members of the Society for Dermatology Hospitalists to elucidate the contributions of dermatologists in the inpatient setting, which has been accomplished primarily by defining and characterizing the types of patients that dermatology hospitalists care for and, more recently, by demonstrating the improved outcomes that result from expert consultation.

Breadth of Inpatient Dermatologic Consultations

With the adaptation of dermatology consultation services, the scope of practice has shifted from the skilled management of chronic dermatoses to one with an emphasis on the identification of various acute dermatologic diseases. Although the extent of such acute disease states in the inpatient setting is vast, it is interesting to note that the majority of consultations are for common conditions, namely cutaneous infections, venous stasis dermatitis, contact dermatitis, atopic dermatitis, and cutaneous drug eruptions (Table).^4,5

Moreover, for the services that obtain dermatologic consultation, the majority of requests originate from internal medicine and hematology/oncology.^4,5 Although internal medicine often is the largest-represented specialty in the hospital and provides a proportional amount of dermatology consultations, hematology/oncology patients represent a distinct cohort who are prone to unique mucocutaneous dermatoses related to underlying malignancies, immunosuppression, and cancer-specific therapies (eg, chemotherapy, immunotherapy, stem cell transplantation). Within this subset of patients, cutaneous infections and drug eruptions constitute the majority of cases, while graft-versus-host disease and neutrophilic dermatoses account for a smaller percentage of dermatologic disease in this population. Given the complex and uncommon nature of these dermatoses, timely intervention by a dermatologist can have a considerable impact on morbidity and mortality associated with such disease states.^6,7

Among pediatric patients, dermatology consultation patterns mimic those seen among adult patients, with common conditions such as atopic dermatitis and contact dermatitis representing the majority of consultations.^8-11 Vascular lesions further represent a unique source of consultation among pediatric patients. Although they often are considered an outpatient concern, one group found that the majority of inpatient consultations for vascular lesions led to early identification of a syndromic association and/or complication (eg, ulceration).¹⁰ Identifying these cases in the hospital provides early opportunities for intervention and multidisciplinary care.

Adding Value to the Care of Hospitalized Patients

Following other inpatient models, hospitalist dermatology has begun to demonstrate feasibility, advances in quality improvement, and most importantly improved health care outcomes. In an effort to better characterize the enhancement of such health care delivery, recent literature around the impact of inpatient dermatology consultation has centered on improving key objective hospital-based quality measures, namely diagnosis and management as well as hospital length of stay (LOS) and readmission rates.^5,12-18

When identifying cutaneous disease, recent evidence points to the increased diagnostic accuracy by way of dermatology consultation. Specifically, diagnoses were changed 30% to 70% of the time when consultations were provided.^6,12-15 Interestingly, misdiagnosis regularly centered on common diagnoses, specifically cellulitis, stasis dermatitis, and hypersensitivity reactions.^6,12-16 In a multi-institutional retrospective study that examined the national incidence of cellulitis misdiagnosis, the authors found that when a dermatology consultation for presumed cellulitis was called, approximately 75% (N=55) of cases represented mimickers of cellulitis, such as stasis dermatitis, contact dermatitis, and cutaneous fungal infections. Moreover, in more than 38% (N=21) of such cellulitis consultations, patients often had more than one ongoing disease process, further speaking to the diagnostic accuracy obtained from expert consultation.¹⁶ The result of such misdiagnosis is not trivial, as unnecessary hospital admission or inappropriate treatment due to misdiagnosis of cutaneous disease often leads to avoidable complications and preventable health care spending. In a cross-sectional analysis of patients diagnosed with presumed lower extremity cellulitis (N=259), approximately 30% were misdiagnosed. In these cases, more than 90% of patients received unnecessary antibiotics, with approximately 30% of them experiencing a complication or avoidable utilization of health care related to their misdiagnosis.¹⁷

Along with the profound impact on diagnostic accuracy, management and treatment are almost universally affected after dermatology consultation.^5,12-14 Such findings bear importance on optimizing hospital LOS as well as readmission rates. For hospital LOS, a recent study demonstrated reductions in LOS by 2.64 days as well as 1-year cutaneous disease-specific readmissions for patients who received dermatologic consultation for their inflammatory skin disease.¹⁸ Similarly, in a recent prospective cohort study of patients diagnosed with presumed lower extremity cellulitis, hospital LOS decreased by 2 days following a diagnosis of pseudocellulitis via timely dermatologic consultation. Across the United States, such reductions in LOS associated with unnecessary hospitalization due to pseudocellulitis can result in annual health care savings of $100 to $200 million.¹³ As such, early dermatologic intervention plays a vital role in diagnostic accuracy, appropriate treatment implementation, expedited discharge, and the overall economics of health care delivery and utilization, thereby supporting the utility of clinical decision support through expert consultation.

Conclusion

There is a clear and distinct value that results in having specialized inpatient dermatology services. Such expert consultation enhances quality of care and reduces health care costs. Although the implementation and success of inpatient dermatology services has primarily been observed at large hospitals/tertiary care centers, there is incredible potential to further our impact through engagement in our community hospitals. With that said, all practicing dermatologists should feel empowered to employ their expert skillset in their own communities, as such access to care and specialty support is desperately needed and can remarkably impact health care outcomes. Moreover, in addition to the direct impact on health care delivery and economics, the intangible benefits of an inpatient dermatology presence are innumerable, as opportunities to promote quality research and improve trainee education also demonstrate our value. These facets together provide a positive perspective on the potential contribution that our field can have on shaping the outlook of hospital medicine. As such, in addition to enjoying the current renaissance of inpatient dermatology, it is imperative that dermatologists build on this momentum and invest in the future of consultative dermatology.

The practice of inpatient dermatology has a rich history rooted in specialized hospital wards that housed patients with chronic dermatoses. Because systemic agents were limited, the care of these patients required skilled nursing and a distinctive knowledge of the application of numerous topical agents, including washes, baths, powders, lotions, and pastes¹; however, with the evolving nature of health care in the last half a century, such dermatologic inpatient units are now rare, with only 2 units remaining in the United States, specifically at the Mayo Clinic in Minnesota and at the University of Miami.²

Although the shift away from a primary dermatologic admitting service is likely multifactorial, what is more sobering is that the majority of inpatients with dermatologic disorders are cared for by nondermatologists.² Although the dynamics for such a diminished presence are due to various personal and professional concerns, the essential outcome for patients hospitalized with a cutaneous concern—whether directly related to their hospitalization or iatrogenic in nature—is the potential for suboptimal care.³

Fortunately, the practice of inpatient dermatology currently is undergoing a renaissance. With this renewed interest in hospital-based dermatology, there is a growing body of evidence that demonstrates how the dermatology hospitalist has become a vital member of the inpatient team, adding value to the care of patients across all specialties.

To explore the impact of consultative dermatology services, there has been a push by members of the Society for Dermatology Hospitalists to elucidate the contributions of dermatologists in the inpatient setting, which has been accomplished primarily by defining and characterizing the types of patients that dermatology hospitalists care for and, more recently, by demonstrating the improved outcomes that result from expert consultation.

Breadth of Inpatient Dermatologic Consultations

With the adaptation of dermatology consultation services, the scope of practice has shifted from the skilled management of chronic dermatoses to one with an emphasis on the identification of various acute dermatologic diseases. Although the extent of such acute disease states in the inpatient setting is vast, it is interesting to note that the majority of consultations are for common conditions, namely cutaneous infections, venous stasis dermatitis, contact dermatitis, atopic dermatitis, and cutaneous drug eruptions (Table).^4,5

Moreover, for the services that obtain dermatologic consultation, the majority of requests originate from internal medicine and hematology/oncology.^4,5 Although internal medicine often is the largest-represented specialty in the hospital and provides a proportional amount of dermatology consultations, hematology/oncology patients represent a distinct cohort who are prone to unique mucocutaneous dermatoses related to underlying malignancies, immunosuppression, and cancer-specific therapies (eg, chemotherapy, immunotherapy, stem cell transplantation). Within this subset of patients, cutaneous infections and drug eruptions constitute the majority of cases, while graft-versus-host disease and neutrophilic dermatoses account for a smaller percentage of dermatologic disease in this population. Given the complex and uncommon nature of these dermatoses, timely intervention by a dermatologist can have a considerable impact on morbidity and mortality associated with such disease states.^6,7

Among pediatric patients, dermatology consultation patterns mimic those seen among adult patients, with common conditions such as atopic dermatitis and contact dermatitis representing the majority of consultations.^8-11 Vascular lesions further represent a unique source of consultation among pediatric patients. Although they often are considered an outpatient concern, one group found that the majority of inpatient consultations for vascular lesions led to early identification of a syndromic association and/or complication (eg, ulceration).¹⁰ Identifying these cases in the hospital provides early opportunities for intervention and multidisciplinary care.

Adding Value to the Care of Hospitalized Patients

Following other inpatient models, hospitalist dermatology has begun to demonstrate feasibility, advances in quality improvement, and most importantly improved health care outcomes. In an effort to better characterize the enhancement of such health care delivery, recent literature around the impact of inpatient dermatology consultation has centered on improving key objective hospital-based quality measures, namely diagnosis and management as well as hospital length of stay (LOS) and readmission rates.^5,12-18

When identifying cutaneous disease, recent evidence points to the increased diagnostic accuracy by way of dermatology consultation. Specifically, diagnoses were changed 30% to 70% of the time when consultations were provided.^6,12-15 Interestingly, misdiagnosis regularly centered on common diagnoses, specifically cellulitis, stasis dermatitis, and hypersensitivity reactions.^6,12-16 In a multi-institutional retrospective study that examined the national incidence of cellulitis misdiagnosis, the authors found that when a dermatology consultation for presumed cellulitis was called, approximately 75% (N=55) of cases represented mimickers of cellulitis, such as stasis dermatitis, contact dermatitis, and cutaneous fungal infections. Moreover, in more than 38% (N=21) of such cellulitis consultations, patients often had more than one ongoing disease process, further speaking to the diagnostic accuracy obtained from expert consultation.¹⁶ The result of such misdiagnosis is not trivial, as unnecessary hospital admission or inappropriate treatment due to misdiagnosis of cutaneous disease often leads to avoidable complications and preventable health care spending. In a cross-sectional analysis of patients diagnosed with presumed lower extremity cellulitis (N=259), approximately 30% were misdiagnosed. In these cases, more than 90% of patients received unnecessary antibiotics, with approximately 30% of them experiencing a complication or avoidable utilization of health care related to their misdiagnosis.¹⁷

Along with the profound impact on diagnostic accuracy, management and treatment are almost universally affected after dermatology consultation.^5,12-14 Such findings bear importance on optimizing hospital LOS as well as readmission rates. For hospital LOS, a recent study demonstrated reductions in LOS by 2.64 days as well as 1-year cutaneous disease-specific readmissions for patients who received dermatologic consultation for their inflammatory skin disease.¹⁸ Similarly, in a recent prospective cohort study of patients diagnosed with presumed lower extremity cellulitis, hospital LOS decreased by 2 days following a diagnosis of pseudocellulitis via timely dermatologic consultation. Across the United States, such reductions in LOS associated with unnecessary hospitalization due to pseudocellulitis can result in annual health care savings of $100 to $200 million.¹³ As such, early dermatologic intervention plays a vital role in diagnostic accuracy, appropriate treatment implementation, expedited discharge, and the overall economics of health care delivery and utilization, thereby supporting the utility of clinical decision support through expert consultation.

Conclusion

There is a clear and distinct value that results in having specialized inpatient dermatology services. Such expert consultation enhances quality of care and reduces health care costs. Although the implementation and success of inpatient dermatology services has primarily been observed at large hospitals/tertiary care centers, there is incredible potential to further our impact through engagement in our community hospitals. With that said, all practicing dermatologists should feel empowered to employ their expert skillset in their own communities, as such access to care and specialty support is desperately needed and can remarkably impact health care outcomes. Moreover, in addition to the direct impact on health care delivery and economics, the intangible benefits of an inpatient dermatology presence are innumerable, as opportunities to promote quality research and improve trainee education also demonstrate our value. These facets together provide a positive perspective on the potential contribution that our field can have on shaping the outlook of hospital medicine. As such, in addition to enjoying the current renaissance of inpatient dermatology, it is imperative that dermatologists build on this momentum and invest in the future of consultative dermatology.

The practice of inpatient dermatology has a rich history rooted in specialized hospital wards that housed patients with chronic dermatoses. Because systemic agents were limited, the care of these patients required skilled nursing and a distinctive knowledge of the application of numerous topical agents, including washes, baths, powders, lotions, and pastes¹; however, with the evolving nature of health care in the last half a century, such dermatologic inpatient units are now rare, with only 2 units remaining in the United States, specifically at the Mayo Clinic in Minnesota and at the University of Miami.²

Although the shift away from a primary dermatologic admitting service is likely multifactorial, what is more sobering is that the majority of inpatients with dermatologic disorders are cared for by nondermatologists.² Although the dynamics for such a diminished presence are due to various personal and professional concerns, the essential outcome for patients hospitalized with a cutaneous concern—whether directly related to their hospitalization or iatrogenic in nature—is the potential for suboptimal care.³

Fortunately, the practice of inpatient dermatology currently is undergoing a renaissance. With this renewed interest in hospital-based dermatology, there is a growing body of evidence that demonstrates how the dermatology hospitalist has become a vital member of the inpatient team, adding value to the care of patients across all specialties.

To explore the impact of consultative dermatology services, there has been a push by members of the Society for Dermatology Hospitalists to elucidate the contributions of dermatologists in the inpatient setting, which has been accomplished primarily by defining and characterizing the types of patients that dermatology hospitalists care for and, more recently, by demonstrating the improved outcomes that result from expert consultation.

Breadth of Inpatient Dermatologic Consultations

With the adaptation of dermatology consultation services, the scope of practice has shifted from the skilled management of chronic dermatoses to one with an emphasis on the identification of various acute dermatologic diseases. Although the extent of such acute disease states in the inpatient setting is vast, it is interesting to note that the majority of consultations are for common conditions, namely cutaneous infections, venous stasis dermatitis, contact dermatitis, atopic dermatitis, and cutaneous drug eruptions (Table).^4,5

Moreover, for the services that obtain dermatologic consultation, the majority of requests originate from internal medicine and hematology/oncology.^4,5 Although internal medicine often is the largest-represented specialty in the hospital and provides a proportional amount of dermatology consultations, hematology/oncology patients represent a distinct cohort who are prone to unique mucocutaneous dermatoses related to underlying malignancies, immunosuppression, and cancer-specific therapies (eg, chemotherapy, immunotherapy, stem cell transplantation). Within this subset of patients, cutaneous infections and drug eruptions constitute the majority of cases, while graft-versus-host disease and neutrophilic dermatoses account for a smaller percentage of dermatologic disease in this population. Given the complex and uncommon nature of these dermatoses, timely intervention by a dermatologist can have a considerable impact on morbidity and mortality associated with such disease states.^6,7

Among pediatric patients, dermatology consultation patterns mimic those seen among adult patients, with common conditions such as atopic dermatitis and contact dermatitis representing the majority of consultations.^8-11 Vascular lesions further represent a unique source of consultation among pediatric patients. Although they often are considered an outpatient concern, one group found that the majority of inpatient consultations for vascular lesions led to early identification of a syndromic association and/or complication (eg, ulceration).¹⁰ Identifying these cases in the hospital provides early opportunities for intervention and multidisciplinary care.

Adding Value to the Care of Hospitalized Patients

Following other inpatient models, hospitalist dermatology has begun to demonstrate feasibility, advances in quality improvement, and most importantly improved health care outcomes. In an effort to better characterize the enhancement of such health care delivery, recent literature around the impact of inpatient dermatology consultation has centered on improving key objective hospital-based quality measures, namely diagnosis and management as well as hospital length of stay (LOS) and readmission rates.^5,12-18

When identifying cutaneous disease, recent evidence points to the increased diagnostic accuracy by way of dermatology consultation. Specifically, diagnoses were changed 30% to 70% of the time when consultations were provided.^6,12-15 Interestingly, misdiagnosis regularly centered on common diagnoses, specifically cellulitis, stasis dermatitis, and hypersensitivity reactions.^6,12-16 In a multi-institutional retrospective study that examined the national incidence of cellulitis misdiagnosis, the authors found that when a dermatology consultation for presumed cellulitis was called, approximately 75% (N=55) of cases represented mimickers of cellulitis, such as stasis dermatitis, contact dermatitis, and cutaneous fungal infections. Moreover, in more than 38% (N=21) of such cellulitis consultations, patients often had more than one ongoing disease process, further speaking to the diagnostic accuracy obtained from expert consultation.¹⁶ The result of such misdiagnosis is not trivial, as unnecessary hospital admission or inappropriate treatment due to misdiagnosis of cutaneous disease often leads to avoidable complications and preventable health care spending. In a cross-sectional analysis of patients diagnosed with presumed lower extremity cellulitis (N=259), approximately 30% were misdiagnosed. In these cases, more than 90% of patients received unnecessary antibiotics, with approximately 30% of them experiencing a complication or avoidable utilization of health care related to their misdiagnosis.¹⁷

Along with the profound impact on diagnostic accuracy, management and treatment are almost universally affected after dermatology consultation.^5,12-14 Such findings bear importance on optimizing hospital LOS as well as readmission rates. For hospital LOS, a recent study demonstrated reductions in LOS by 2.64 days as well as 1-year cutaneous disease-specific readmissions for patients who received dermatologic consultation for their inflammatory skin disease.¹⁸ Similarly, in a recent prospective cohort study of patients diagnosed with presumed lower extremity cellulitis, hospital LOS decreased by 2 days following a diagnosis of pseudocellulitis via timely dermatologic consultation. Across the United States, such reductions in LOS associated with unnecessary hospitalization due to pseudocellulitis can result in annual health care savings of $100 to $200 million.¹³ As such, early dermatologic intervention plays a vital role in diagnostic accuracy, appropriate treatment implementation, expedited discharge, and the overall economics of health care delivery and utilization, thereby supporting the utility of clinical decision support through expert consultation.

Conclusion

There is a clear and distinct value that results in having specialized inpatient dermatology services. Such expert consultation enhances quality of care and reduces health care costs. Although the implementation and success of inpatient dermatology services has primarily been observed at large hospitals/tertiary care centers, there is incredible potential to further our impact through engagement in our community hospitals. With that said, all practicing dermatologists should feel empowered to employ their expert skillset in their own communities, as such access to care and specialty support is desperately needed and can remarkably impact health care outcomes. Moreover, in addition to the direct impact on health care delivery and economics, the intangible benefits of an inpatient dermatology presence are innumerable, as opportunities to promote quality research and improve trainee education also demonstrate our value. These facets together provide a positive perspective on the potential contribution that our field can have on shaping the outlook of hospital medicine. As such, in addition to enjoying the current renaissance of inpatient dermatology, it is imperative that dermatologists build on this momentum and invest in the future of consultative dermatology.

The Diagnosis: Cutaneous Metastases

Cutaneous metastases (CMs) can present in an otherwise asymptomatic patient as the only sign of an underlying disease process. In women, the most common cause of CM is breast carcinoma.^1-3 Cutaneous metastases are found in approximately 25% of all patients with breast carcinoma,¹ and breast carcinomas represent approximately 69% of all CMs found in women (Table 1).² Cutaneous metastatic breast carcinoma (CMBC) is associated with a poor prognosis with a mean survival of approximately 6 months at the time of diagnosis.^1,3 It commonly presents as a collection of flesh-colored, firm, asymptomatic, and rapidly appearing papules and nodules that can resemble cysts or fibrous tumors.^1,3,4 They typically are located on the chest wall or abdomen near the site of the underlying malignancy.^1-3 The histologic features of CMBC can include hyperchromatic tumor cells infiltrating between the collagen fibers in a characteristic single file manner,^3,5 giving the appearance of a busy dermis, a nonspecific term to describe a focally hypercellular dermis at low-power magnification (Table 2).^5,6 Cords and clusters of atypical cells with intracytoplasmic vacuoles or well-developed ducts also can be seen (quiz image [inset]). The carcinoma en cuirasse subtype of CMBC is characterized by a fibrotic scarlike plaque on the chest wall.^1,3 If a punch biopsy is obtained, the specimen typically appears rectangular rather than tapered because of the sclerotic dermal collagen.⁶ In contrast, inflammatory carcinoma (carcinoma erysipelatoides) presents as an erythematous plaque resembling cellulitis due to the lymphatics being congested by tumor cells.³ Immunohistochemistry is a valuable tool in diagnosis. Positive staining is seen with cytokeratin 7, gross cystic disease fluid protein-15, mammaglobin, and GATA-3.^1,3,6

Kaposi sarcoma (KS) is a low-grade endothelial malignancy associated with human herpesvirus 8.^3,4 Kaposi sarcoma can be divided into 4 main subtypes: classic KS, African KS, AIDS-related KS, and immunosuppression-associated KS that occurs in patients with diseases such as human immunodeficiency virus. The cutaneous lesions are similar between subtypes and present as dark reddish purple macules that may enlarge or become nodular lesions.^3,4 Histologically, 3 distinct stages of progression are described: patch, plaque, and tumor. The plaque stage has the appearance of a busy dermis due to the rapid proliferation of vascular structures within the dermis.^3,6 A useful histologic feature known as the promontory sign can be seen as the proliferating tumor causes preexisting structures to project into vascular spaces (Figure 1).⁶ Immunohistochemistry for the endothelial and lymphatic markers CD31 and D2-40, respectively, are positive and may aid in the diagnosis.³ Staining for the latent nuclear antigen-1 of human herpesvirus 8 is a highly specific marker used to diagnose KS and can further distinguish it from the other busy dermis lesions.³ 

Granuloma annulare (GA) is characterized by rings of small, firm, pink to flesh-colored papules with a variable disease duration.⁴ Histologically, the interstitial variant of GA is characterized by a scattered inflammatory infiltrate consisting of histiocytes and lymphocytes located between altered collagen fibers in the superficial to mid dermis (Figure 2).^3,6 Occasional eosinophils and increased dermal mucin are useful features to distinguish interstitial GA from other entities in the busy dermis differential.⁷

Scleromyxedema, also known as generalized lichen myxedematosus, is a rare mucinosis.^3,8 Although its pathogenesis is unknown, it has been suggested that paraproteins related to the underlying gammopathy act to stimulate fibroblast proliferation and mucin overproduction.⁸ Clinically, characteristic widespread firm, waxy, dome-shaped papules are present over the head, upper trunk, and extremities.^3,8 Histologically, scleromyxedema is characterized by increased dermal fibroblasts, mucin, and fibrosis, leading to the appearance of a busy dermis (Figure 3).^3,6

Neurofibromas are common benign peripheral nerve sheath tumors that can occur sporadically or in the setting of neurofibromatosis.^3-5 They present as soft, flesh-colored papules or nodules most commonly located on the trunk and limbs.⁴ Histologically, neurofibromas are nonencapsulated tumors composed of abundant spindle cells with comma-shaped nuclei diffusely arranged in a pale myxoid stroma (Figure 4). Scattered mast cells can be visualized at higher magnification.^3,6

The Diagnosis: Cutaneous Metastases

Cutaneous metastases (CMs) can present in an otherwise asymptomatic patient as the only sign of an underlying disease process. In women, the most common cause of CM is breast carcinoma.^1-3 Cutaneous metastases are found in approximately 25% of all patients with breast carcinoma,¹ and breast carcinomas represent approximately 69% of all CMs found in women (Table 1).² Cutaneous metastatic breast carcinoma (CMBC) is associated with a poor prognosis with a mean survival of approximately 6 months at the time of diagnosis.^1,3 It commonly presents as a collection of flesh-colored, firm, asymptomatic, and rapidly appearing papules and nodules that can resemble cysts or fibrous tumors.^1,3,4 They typically are located on the chest wall or abdomen near the site of the underlying malignancy.^1-3 The histologic features of CMBC can include hyperchromatic tumor cells infiltrating between the collagen fibers in a characteristic single file manner,^3,5 giving the appearance of a busy dermis, a nonspecific term to describe a focally hypercellular dermis at low-power magnification (Table 2).^5,6 Cords and clusters of atypical cells with intracytoplasmic vacuoles or well-developed ducts also can be seen (quiz image [inset]). The carcinoma en cuirasse subtype of CMBC is characterized by a fibrotic scarlike plaque on the chest wall.^1,3 If a punch biopsy is obtained, the specimen typically appears rectangular rather than tapered because of the sclerotic dermal collagen.⁶ In contrast, inflammatory carcinoma (carcinoma erysipelatoides) presents as an erythematous plaque resembling cellulitis due to the lymphatics being congested by tumor cells.³ Immunohistochemistry is a valuable tool in diagnosis. Positive staining is seen with cytokeratin 7, gross cystic disease fluid protein-15, mammaglobin, and GATA-3.^1,3,6

Kaposi sarcoma (KS) is a low-grade endothelial malignancy associated with human herpesvirus 8.^3,4 Kaposi sarcoma can be divided into 4 main subtypes: classic KS, African KS, AIDS-related KS, and immunosuppression-associated KS that occurs in patients with diseases such as human immunodeficiency virus. The cutaneous lesions are similar between subtypes and present as dark reddish purple macules that may enlarge or become nodular lesions.^3,4 Histologically, 3 distinct stages of progression are described: patch, plaque, and tumor. The plaque stage has the appearance of a busy dermis due to the rapid proliferation of vascular structures within the dermis.^3,6 A useful histologic feature known as the promontory sign can be seen as the proliferating tumor causes preexisting structures to project into vascular spaces (Figure 1).⁶ Immunohistochemistry for the endothelial and lymphatic markers CD31 and D2-40, respectively, are positive and may aid in the diagnosis.³ Staining for the latent nuclear antigen-1 of human herpesvirus 8 is a highly specific marker used to diagnose KS and can further distinguish it from the other busy dermis lesions.³ 

Granuloma annulare (GA) is characterized by rings of small, firm, pink to flesh-colored papules with a variable disease duration.⁴ Histologically, the interstitial variant of GA is characterized by a scattered inflammatory infiltrate consisting of histiocytes and lymphocytes located between altered collagen fibers in the superficial to mid dermis (Figure 2).^3,6 Occasional eosinophils and increased dermal mucin are useful features to distinguish interstitial GA from other entities in the busy dermis differential.⁷

Scleromyxedema, also known as generalized lichen myxedematosus, is a rare mucinosis.^3,8 Although its pathogenesis is unknown, it has been suggested that paraproteins related to the underlying gammopathy act to stimulate fibroblast proliferation and mucin overproduction.⁸ Clinically, characteristic widespread firm, waxy, dome-shaped papules are present over the head, upper trunk, and extremities.^3,8 Histologically, scleromyxedema is characterized by increased dermal fibroblasts, mucin, and fibrosis, leading to the appearance of a busy dermis (Figure 3).^3,6

Neurofibromas are common benign peripheral nerve sheath tumors that can occur sporadically or in the setting of neurofibromatosis.^3-5 They present as soft, flesh-colored papules or nodules most commonly located on the trunk and limbs.⁴ Histologically, neurofibromas are nonencapsulated tumors composed of abundant spindle cells with comma-shaped nuclei diffusely arranged in a pale myxoid stroma (Figure 4). Scattered mast cells can be visualized at higher magnification.^3,6

The Diagnosis: Cutaneous Metastases

Cutaneous metastases (CMs) can present in an otherwise asymptomatic patient as the only sign of an underlying disease process. In women, the most common cause of CM is breast carcinoma.^1-3 Cutaneous metastases are found in approximately 25% of all patients with breast carcinoma,¹ and breast carcinomas represent approximately 69% of all CMs found in women (Table 1).² Cutaneous metastatic breast carcinoma (CMBC) is associated with a poor prognosis with a mean survival of approximately 6 months at the time of diagnosis.^1,3 It commonly presents as a collection of flesh-colored, firm, asymptomatic, and rapidly appearing papules and nodules that can resemble cysts or fibrous tumors.^1,3,4 They typically are located on the chest wall or abdomen near the site of the underlying malignancy.^1-3 The histologic features of CMBC can include hyperchromatic tumor cells infiltrating between the collagen fibers in a characteristic single file manner,^3,5 giving the appearance of a busy dermis, a nonspecific term to describe a focally hypercellular dermis at low-power magnification (Table 2).^5,6 Cords and clusters of atypical cells with intracytoplasmic vacuoles or well-developed ducts also can be seen (quiz image [inset]). The carcinoma en cuirasse subtype of CMBC is characterized by a fibrotic scarlike plaque on the chest wall.^1,3 If a punch biopsy is obtained, the specimen typically appears rectangular rather than tapered because of the sclerotic dermal collagen.⁶ In contrast, inflammatory carcinoma (carcinoma erysipelatoides) presents as an erythematous plaque resembling cellulitis due to the lymphatics being congested by tumor cells.³ Immunohistochemistry is a valuable tool in diagnosis. Positive staining is seen with cytokeratin 7, gross cystic disease fluid protein-15, mammaglobin, and GATA-3.^1,3,6

Kaposi sarcoma (KS) is a low-grade endothelial malignancy associated with human herpesvirus 8.^3,4 Kaposi sarcoma can be divided into 4 main subtypes: classic KS, African KS, AIDS-related KS, and immunosuppression-associated KS that occurs in patients with diseases such as human immunodeficiency virus. The cutaneous lesions are similar between subtypes and present as dark reddish purple macules that may enlarge or become nodular lesions.^3,4 Histologically, 3 distinct stages of progression are described: patch, plaque, and tumor. The plaque stage has the appearance of a busy dermis due to the rapid proliferation of vascular structures within the dermis.^3,6 A useful histologic feature known as the promontory sign can be seen as the proliferating tumor causes preexisting structures to project into vascular spaces (Figure 1).⁶ Immunohistochemistry for the endothelial and lymphatic markers CD31 and D2-40, respectively, are positive and may aid in the diagnosis.³ Staining for the latent nuclear antigen-1 of human herpesvirus 8 is a highly specific marker used to diagnose KS and can further distinguish it from the other busy dermis lesions.³ 

Granuloma annulare (GA) is characterized by rings of small, firm, pink to flesh-colored papules with a variable disease duration.⁴ Histologically, the interstitial variant of GA is characterized by a scattered inflammatory infiltrate consisting of histiocytes and lymphocytes located between altered collagen fibers in the superficial to mid dermis (Figure 2).^3,6 Occasional eosinophils and increased dermal mucin are useful features to distinguish interstitial GA from other entities in the busy dermis differential.⁷

Scleromyxedema, also known as generalized lichen myxedematosus, is a rare mucinosis.^3,8 Although its pathogenesis is unknown, it has been suggested that paraproteins related to the underlying gammopathy act to stimulate fibroblast proliferation and mucin overproduction.⁸ Clinically, characteristic widespread firm, waxy, dome-shaped papules are present over the head, upper trunk, and extremities.^3,8 Histologically, scleromyxedema is characterized by increased dermal fibroblasts, mucin, and fibrosis, leading to the appearance of a busy dermis (Figure 3).^3,6

Neurofibromas are common benign peripheral nerve sheath tumors that can occur sporadically or in the setting of neurofibromatosis.^3-5 They present as soft, flesh-colored papules or nodules most commonly located on the trunk and limbs.⁴ Histologically, neurofibromas are nonencapsulated tumors composed of abundant spindle cells with comma-shaped nuclei diffusely arranged in a pale myxoid stroma (Figure 4). Scattered mast cells can be visualized at higher magnification.^3,6

Vitiligo is a disfiguring skin condition that is thought to result from autoimmune destruction of melanocytes in the skin, leading to patchy depigmentation. The prevalence of vitiligo is estimated at 1% worldwide.¹ Once seen as merely a cosmetic disorder, it is increasingly recognized for its devastating psychological effects. As skin quality, texture, and color are a few of the first things people notice about others, skin plays a major role in our daily interactions with the world. Vitiligo often affects the face and other visible areas of the body; thus, it is associated with impaired quality of life, and affected individuals often experience psychosocial impairment including anxiety, depression, stigmatization, and self-harm ideation.² Indeed, vitiligo is a condition with not only a visible skin component but a deeper psychological component that also is important to recognize and address. However, due in large part to recent exposure to vitiligo through mainstream media, general understanding about and attitudes toward this condition are changing. As a result, vitiligo has seen a surge in outreach by those affected by the disease.

Perhaps the most well-known current face of vitiligo is Chantelle Brown-Young, a black fashion model, activist, and vitiligo spokesperson known professionally as Winnie Harlow. Diagnosed with vitiligo in childhood, she revealed she was teased and bullied and at one point contemplated suicide. “The continuous harassment and the despair that [vitiligo] brought on my life was so unbearably dehumanizing that I wanted to kill myself,” she disclosed.³ After competing on America’s Next Top Model in 2014, Winnie Harlow became a household name for redefining global standards of beauty and, in her own words, accepting the differences that make us unique and authentic.⁴ She went on to speak at the Dove Self-Esteem Project panel at the 2015 Women in the World London Summit and was presented with the Role Model award at the Portuguese GQ Men of the Year event that same year.⁵

More recently, Amy Deanna, a model with vitiligo, was featured in videos for CoverGirl’s 2018 “I Am What I Make Up” campaign in which she is shown enhancing her various skin tones rather than hiding them by applying both light and dark shades of makeup on her face. In a press release she stated, “Vitiligo awareness is something that is very important to me. Being given a platform to [raise awareness] means so much.”⁶

Additionally, Brock Elbank, a London-based photographer, recently launched a photograph series of men and women with vitiligo on the digital platform Instagram.⁷ In a recent interview he stated, “I see beauty in what many see as different. Unique individuals who stand out from the crowd are what inspire me to do what I do.”⁷

Lee Thomas, a television broadcaster and author of the book Turning White: A Memoir of Change is yet another example of a vitiligo patient who recently stopped hiding his condition. He admitted he has had people refuse to shake his hand due to his condition but has used the experience to educate others. He stated, “Because I’m in this position, I think this is where my next thing is supposed to be. It’s supposed to be about sharing and helping, and hopefully leaving the planet a little better for everybody else who comes along with vitiligo.”⁸ Thomas is dedicated to inspiring others with the condition and started the Clarity Lee Thomas Foundation to provide emotional and mental support to those with vitiligo.

Critics may say this vitiligo movement is merely another example of exploitation of what is unique or different by mainstream media and the fashion industry, similar to prior movements for plus-sized models, natural hairstyles in black women, and transgender identification. Even if partially true, the ultimate effect has been an increase in attention and representation of individuals with vitiligo in mainstream media. At the time this article was being published (September 2018), an Instagram search for #vitiligo yielded approximately 226,000 posts. For comparison with other much more common dermatologic conditions, #eczema returned approximately 958,000 results, #moles returned approximately 65,000 results, and #skincancer returned approximately 104,000 results. Additionally, the Vitiligo Research Foundation currently has more than 5000 followers on Instagram, which is as many as the Melanoma Research Foundation and almost twice as many as the Skin Cancer Foundation, supporting the idea that mainstream representation of individuals with vitiligo is contributing to raising awareness and backing of organizations aimed at making advancements in this area of dermatology.

As more individuals gain an understanding and curiosity about this disease, perhaps more research and investigation will be done to improve treatment options and outcomes for patients with vitiligo. With this movement, perhaps vitiligo patients will feel more comfortable and confident in their skin.

Vitiligo is a disfiguring skin condition that is thought to result from autoimmune destruction of melanocytes in the skin, leading to patchy depigmentation. The prevalence of vitiligo is estimated at 1% worldwide.¹ Once seen as merely a cosmetic disorder, it is increasingly recognized for its devastating psychological effects. As skin quality, texture, and color are a few of the first things people notice about others, skin plays a major role in our daily interactions with the world. Vitiligo often affects the face and other visible areas of the body; thus, it is associated with impaired quality of life, and affected individuals often experience psychosocial impairment including anxiety, depression, stigmatization, and self-harm ideation.² Indeed, vitiligo is a condition with not only a visible skin component but a deeper psychological component that also is important to recognize and address. However, due in large part to recent exposure to vitiligo through mainstream media, general understanding about and attitudes toward this condition are changing. As a result, vitiligo has seen a surge in outreach by those affected by the disease.

Perhaps the most well-known current face of vitiligo is Chantelle Brown-Young, a black fashion model, activist, and vitiligo spokesperson known professionally as Winnie Harlow. Diagnosed with vitiligo in childhood, she revealed she was teased and bullied and at one point contemplated suicide. “The continuous harassment and the despair that [vitiligo] brought on my life was so unbearably dehumanizing that I wanted to kill myself,” she disclosed.³ After competing on America’s Next Top Model in 2014, Winnie Harlow became a household name for redefining global standards of beauty and, in her own words, accepting the differences that make us unique and authentic.⁴ She went on to speak at the Dove Self-Esteem Project panel at the 2015 Women in the World London Summit and was presented with the Role Model award at the Portuguese GQ Men of the Year event that same year.⁵

More recently, Amy Deanna, a model with vitiligo, was featured in videos for CoverGirl’s 2018 “I Am What I Make Up” campaign in which she is shown enhancing her various skin tones rather than hiding them by applying both light and dark shades of makeup on her face. In a press release she stated, “Vitiligo awareness is something that is very important to me. Being given a platform to [raise awareness] means so much.”⁶

Additionally, Brock Elbank, a London-based photographer, recently launched a photograph series of men and women with vitiligo on the digital platform Instagram.⁷ In a recent interview he stated, “I see beauty in what many see as different. Unique individuals who stand out from the crowd are what inspire me to do what I do.”⁷

Lee Thomas, a television broadcaster and author of the book Turning White: A Memoir of Change is yet another example of a vitiligo patient who recently stopped hiding his condition. He admitted he has had people refuse to shake his hand due to his condition but has used the experience to educate others. He stated, “Because I’m in this position, I think this is where my next thing is supposed to be. It’s supposed to be about sharing and helping, and hopefully leaving the planet a little better for everybody else who comes along with vitiligo.”⁸ Thomas is dedicated to inspiring others with the condition and started the Clarity Lee Thomas Foundation to provide emotional and mental support to those with vitiligo.

Critics may say this vitiligo movement is merely another example of exploitation of what is unique or different by mainstream media and the fashion industry, similar to prior movements for plus-sized models, natural hairstyles in black women, and transgender identification. Even if partially true, the ultimate effect has been an increase in attention and representation of individuals with vitiligo in mainstream media. At the time this article was being published (September 2018), an Instagram search for #vitiligo yielded approximately 226,000 posts. For comparison with other much more common dermatologic conditions, #eczema returned approximately 958,000 results, #moles returned approximately 65,000 results, and #skincancer returned approximately 104,000 results. Additionally, the Vitiligo Research Foundation currently has more than 5000 followers on Instagram, which is as many as the Melanoma Research Foundation and almost twice as many as the Skin Cancer Foundation, supporting the idea that mainstream representation of individuals with vitiligo is contributing to raising awareness and backing of organizations aimed at making advancements in this area of dermatology.

As more individuals gain an understanding and curiosity about this disease, perhaps more research and investigation will be done to improve treatment options and outcomes for patients with vitiligo. With this movement, perhaps vitiligo patients will feel more comfortable and confident in their skin.

Vitiligo is a disfiguring skin condition that is thought to result from autoimmune destruction of melanocytes in the skin, leading to patchy depigmentation. The prevalence of vitiligo is estimated at 1% worldwide.¹ Once seen as merely a cosmetic disorder, it is increasingly recognized for its devastating psychological effects. As skin quality, texture, and color are a few of the first things people notice about others, skin plays a major role in our daily interactions with the world. Vitiligo often affects the face and other visible areas of the body; thus, it is associated with impaired quality of life, and affected individuals often experience psychosocial impairment including anxiety, depression, stigmatization, and self-harm ideation.² Indeed, vitiligo is a condition with not only a visible skin component but a deeper psychological component that also is important to recognize and address. However, due in large part to recent exposure to vitiligo through mainstream media, general understanding about and attitudes toward this condition are changing. As a result, vitiligo has seen a surge in outreach by those affected by the disease.

Perhaps the most well-known current face of vitiligo is Chantelle Brown-Young, a black fashion model, activist, and vitiligo spokesperson known professionally as Winnie Harlow. Diagnosed with vitiligo in childhood, she revealed she was teased and bullied and at one point contemplated suicide. “The continuous harassment and the despair that [vitiligo] brought on my life was so unbearably dehumanizing that I wanted to kill myself,” she disclosed.³ After competing on America’s Next Top Model in 2014, Winnie Harlow became a household name for redefining global standards of beauty and, in her own words, accepting the differences that make us unique and authentic.⁴ She went on to speak at the Dove Self-Esteem Project panel at the 2015 Women in the World London Summit and was presented with the Role Model award at the Portuguese GQ Men of the Year event that same year.⁵

More recently, Amy Deanna, a model with vitiligo, was featured in videos for CoverGirl’s 2018 “I Am What I Make Up” campaign in which she is shown enhancing her various skin tones rather than hiding them by applying both light and dark shades of makeup on her face. In a press release she stated, “Vitiligo awareness is something that is very important to me. Being given a platform to [raise awareness] means so much.”⁶

Additionally, Brock Elbank, a London-based photographer, recently launched a photograph series of men and women with vitiligo on the digital platform Instagram.⁷ In a recent interview he stated, “I see beauty in what many see as different. Unique individuals who stand out from the crowd are what inspire me to do what I do.”⁷

Lee Thomas, a television broadcaster and author of the book Turning White: A Memoir of Change is yet another example of a vitiligo patient who recently stopped hiding his condition. He admitted he has had people refuse to shake his hand due to his condition but has used the experience to educate others. He stated, “Because I’m in this position, I think this is where my next thing is supposed to be. It’s supposed to be about sharing and helping, and hopefully leaving the planet a little better for everybody else who comes along with vitiligo.”⁸ Thomas is dedicated to inspiring others with the condition and started the Clarity Lee Thomas Foundation to provide emotional and mental support to those with vitiligo.

Critics may say this vitiligo movement is merely another example of exploitation of what is unique or different by mainstream media and the fashion industry, similar to prior movements for plus-sized models, natural hairstyles in black women, and transgender identification. Even if partially true, the ultimate effect has been an increase in attention and representation of individuals with vitiligo in mainstream media. At the time this article was being published (September 2018), an Instagram search for #vitiligo yielded approximately 226,000 posts. For comparison with other much more common dermatologic conditions, #eczema returned approximately 958,000 results, #moles returned approximately 65,000 results, and #skincancer returned approximately 104,000 results. Additionally, the Vitiligo Research Foundation currently has more than 5000 followers on Instagram, which is as many as the Melanoma Research Foundation and almost twice as many as the Skin Cancer Foundation, supporting the idea that mainstream representation of individuals with vitiligo is contributing to raising awareness and backing of organizations aimed at making advancements in this area of dermatology.

As more individuals gain an understanding and curiosity about this disease, perhaps more research and investigation will be done to improve treatment options and outcomes for patients with vitiligo. With this movement, perhaps vitiligo patients will feel more comfortable and confident in their skin.

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The Diagnosis: Chromomycosis

Skin scrapings revealed brownish sclerotic bodies. A review of the skin biopsy performed 4 years prior showed florid pseudoepitheliomatous hyperplasia overlying dense mixed inflammatory infiltrates of predominantly granulomatous microabscesses in the dermis. Numerous sclerotic bodies were evident within multinucleated giant cells and scattered among epidermal and dermal microabscesses (Figure). Few atypical basal keratinocytes were noted, but frank pleomorphism and aberrant mitosis was absent.

Chromomycosis is a chronic subcutaneous fungal infection caused by pigmented (dematiaceous) fungi growing in soil, decaying vegetables, and rotting wood. Infection usually occurs via traumatic inoculation from splinters and thorns. Some of the agents responsible include Fonsecaea pedrosoi, Cladophialophora carrionii, and Phialophora verrucosa.¹

Diverse cutaneous manifestations have been observed with 5 different clinical forms: nodules, verrucous hyperkeratotic plaques, cicatricial lesions with central sparing, scaly plaques, and tumoral (cauliflowerlike) lesions.² Of these clinical presentations, verrucous hyperkeratotic plaques are the most common, as seen in our patient. However, this presentation is not exclusive to chromomycosis because many conditions appear similarly, including sporotrichosis, nontuberculous mycobacterial infection, tuberculosis verrucosa cutis, and squamous cell carcinoma (SCC). The presence of small ulcerations may appear as the black dots seen on the plaques of chromomycosis, distinguishing chromomycosis from other conditions. Although this feature may be a fundamental clue for diagnosis, it should be emphasized that in many occasions, clinical differences between chromomycosis and its differentials are subtle. A study involving 9 patients with chromomycosis reported that only 1 was given the initial diagnosis of mycosis. Six patients initially were diagnosed with cutaneous malignancies, 1 patient with viral warts, and another patient with ganglion.³ Therefore, unless there is a high index of suspicion, these conditions may easily be mistaken for others by clinicians who are unfamiliar with their presentations, particularly in the setting of a busy clinic.

Chromomycosis routinely is diagnosed based on histologic examination and culture. Apart from sclerotic bodies, other histopathologic features include an inflammatory infiltrate characterized by neutrophilic microabscesses, multinucleated cells, fibrosis, acanthosis, papillomatosis, hyperkeratosis, and pseudoepitheliomatous hyperplasia (PEH).² Pseudoepitheliomatous hyperplasia is an exaggerated proliferation of the epidermis, usually secondary to chronic inflammatory skin conditions.⁴ Because most verrucous lesions are thought to be neoplastic and carcinomas more commonly are seen and expected in dermatopathology, PEH can sometimes be mistaken for SCC. At times, the squamous epithelium of PEH can appear infiltrative, giving the illusion of well-differentiated SCC.⁵ However, absence of marked cellular atypia and abnormal mitotic activity should suggest otherwise. Thorough scrutiny for a concomitant infective process is necessary to avoid the overdiagnosis of SCC. Special stains for infectious agents such as periodic acid-Schiff and Grocott-Gomori methenamine-silver for fungal spores and Ziehl-Neelsen for acid-fast bacilli may reveal infectious organisms. Multilevel sections of deeper levels also may be essential to uncover sparse organisms.⁶

There is no standard treatment of chromomycosis. Some treatment options are available based on few open clinical studies and expert opinions. Systemic antifungals such as itraconazole or terbinafine most commonly are used with 15% to 80% cure rates.⁷ In invasive refractory cases, a combination of itraconazole and terbinafine has been employed as salvage therapy. Recently, the use of newer azoles such as posaconazole is favored due to its expanded-spectrum profile along with better pharmacodynamics and pharmacokinetic profile versus itraconazole. Physical methods such as cryotherapy, heat therapy, laser therapy, and photodynamic therapy frequently are practiced in conjunction with systemic antifungal therapy.⁸ Surgical procedures such as photocoagulation, Mohs micrographic surgery, and curettage sometimes are recommended for smaller well-defined lesions. Amputation, however, is rarely ever indicated, as there rarely is deep tissue involvement.²

Our case highlights the importance of clinicopathologic correlation in diagnosing squamous epithelial lesions. A high index of clinical suspicion and a wider list of differential diagnoses of verrucous plaques are necessary to minimize pitfalls in diagnosing lesions with squamous proliferation and therefore reduces the need for unnecessary interventions.

The Diagnosis: Chromomycosis

Skin scrapings revealed brownish sclerotic bodies. A review of the skin biopsy performed 4 years prior showed florid pseudoepitheliomatous hyperplasia overlying dense mixed inflammatory infiltrates of predominantly granulomatous microabscesses in the dermis. Numerous sclerotic bodies were evident within multinucleated giant cells and scattered among epidermal and dermal microabscesses (Figure). Few atypical basal keratinocytes were noted, but frank pleomorphism and aberrant mitosis was absent.

Chromomycosis is a chronic subcutaneous fungal infection caused by pigmented (dematiaceous) fungi growing in soil, decaying vegetables, and rotting wood. Infection usually occurs via traumatic inoculation from splinters and thorns. Some of the agents responsible include Fonsecaea pedrosoi, Cladophialophora carrionii, and Phialophora verrucosa.¹

Diverse cutaneous manifestations have been observed with 5 different clinical forms: nodules, verrucous hyperkeratotic plaques, cicatricial lesions with central sparing, scaly plaques, and tumoral (cauliflowerlike) lesions.² Of these clinical presentations, verrucous hyperkeratotic plaques are the most common, as seen in our patient. However, this presentation is not exclusive to chromomycosis because many conditions appear similarly, including sporotrichosis, nontuberculous mycobacterial infection, tuberculosis verrucosa cutis, and squamous cell carcinoma (SCC). The presence of small ulcerations may appear as the black dots seen on the plaques of chromomycosis, distinguishing chromomycosis from other conditions. Although this feature may be a fundamental clue for diagnosis, it should be emphasized that in many occasions, clinical differences between chromomycosis and its differentials are subtle. A study involving 9 patients with chromomycosis reported that only 1 was given the initial diagnosis of mycosis. Six patients initially were diagnosed with cutaneous malignancies, 1 patient with viral warts, and another patient with ganglion.³ Therefore, unless there is a high index of suspicion, these conditions may easily be mistaken for others by clinicians who are unfamiliar with their presentations, particularly in the setting of a busy clinic.

Chromomycosis routinely is diagnosed based on histologic examination and culture. Apart from sclerotic bodies, other histopathologic features include an inflammatory infiltrate characterized by neutrophilic microabscesses, multinucleated cells, fibrosis, acanthosis, papillomatosis, hyperkeratosis, and pseudoepitheliomatous hyperplasia (PEH).² Pseudoepitheliomatous hyperplasia is an exaggerated proliferation of the epidermis, usually secondary to chronic inflammatory skin conditions.⁴ Because most verrucous lesions are thought to be neoplastic and carcinomas more commonly are seen and expected in dermatopathology, PEH can sometimes be mistaken for SCC. At times, the squamous epithelium of PEH can appear infiltrative, giving the illusion of well-differentiated SCC.⁵ However, absence of marked cellular atypia and abnormal mitotic activity should suggest otherwise. Thorough scrutiny for a concomitant infective process is necessary to avoid the overdiagnosis of SCC. Special stains for infectious agents such as periodic acid-Schiff and Grocott-Gomori methenamine-silver for fungal spores and Ziehl-Neelsen for acid-fast bacilli may reveal infectious organisms. Multilevel sections of deeper levels also may be essential to uncover sparse organisms.⁶

There is no standard treatment of chromomycosis. Some treatment options are available based on few open clinical studies and expert opinions. Systemic antifungals such as itraconazole or terbinafine most commonly are used with 15% to 80% cure rates.⁷ In invasive refractory cases, a combination of itraconazole and terbinafine has been employed as salvage therapy. Recently, the use of newer azoles such as posaconazole is favored due to its expanded-spectrum profile along with better pharmacodynamics and pharmacokinetic profile versus itraconazole. Physical methods such as cryotherapy, heat therapy, laser therapy, and photodynamic therapy frequently are practiced in conjunction with systemic antifungal therapy.⁸ Surgical procedures such as photocoagulation, Mohs micrographic surgery, and curettage sometimes are recommended for smaller well-defined lesions. Amputation, however, is rarely ever indicated, as there rarely is deep tissue involvement.²

Our case highlights the importance of clinicopathologic correlation in diagnosing squamous epithelial lesions. A high index of clinical suspicion and a wider list of differential diagnoses of verrucous plaques are necessary to minimize pitfalls in diagnosing lesions with squamous proliferation and therefore reduces the need for unnecessary interventions.

The Diagnosis: Chromomycosis

Skin scrapings revealed brownish sclerotic bodies. A review of the skin biopsy performed 4 years prior showed florid pseudoepitheliomatous hyperplasia overlying dense mixed inflammatory infiltrates of predominantly granulomatous microabscesses in the dermis. Numerous sclerotic bodies were evident within multinucleated giant cells and scattered among epidermal and dermal microabscesses (Figure). Few atypical basal keratinocytes were noted, but frank pleomorphism and aberrant mitosis was absent.

Chromomycosis is a chronic subcutaneous fungal infection caused by pigmented (dematiaceous) fungi growing in soil, decaying vegetables, and rotting wood. Infection usually occurs via traumatic inoculation from splinters and thorns. Some of the agents responsible include Fonsecaea pedrosoi, Cladophialophora carrionii, and Phialophora verrucosa.¹

Diverse cutaneous manifestations have been observed with 5 different clinical forms: nodules, verrucous hyperkeratotic plaques, cicatricial lesions with central sparing, scaly plaques, and tumoral (cauliflowerlike) lesions.² Of these clinical presentations, verrucous hyperkeratotic plaques are the most common, as seen in our patient. However, this presentation is not exclusive to chromomycosis because many conditions appear similarly, including sporotrichosis, nontuberculous mycobacterial infection, tuberculosis verrucosa cutis, and squamous cell carcinoma (SCC). The presence of small ulcerations may appear as the black dots seen on the plaques of chromomycosis, distinguishing chromomycosis from other conditions. Although this feature may be a fundamental clue for diagnosis, it should be emphasized that in many occasions, clinical differences between chromomycosis and its differentials are subtle. A study involving 9 patients with chromomycosis reported that only 1 was given the initial diagnosis of mycosis. Six patients initially were diagnosed with cutaneous malignancies, 1 patient with viral warts, and another patient with ganglion.³ Therefore, unless there is a high index of suspicion, these conditions may easily be mistaken for others by clinicians who are unfamiliar with their presentations, particularly in the setting of a busy clinic.

Chromomycosis routinely is diagnosed based on histologic examination and culture. Apart from sclerotic bodies, other histopathologic features include an inflammatory infiltrate characterized by neutrophilic microabscesses, multinucleated cells, fibrosis, acanthosis, papillomatosis, hyperkeratosis, and pseudoepitheliomatous hyperplasia (PEH).² Pseudoepitheliomatous hyperplasia is an exaggerated proliferation of the epidermis, usually secondary to chronic inflammatory skin conditions.⁴ Because most verrucous lesions are thought to be neoplastic and carcinomas more commonly are seen and expected in dermatopathology, PEH can sometimes be mistaken for SCC. At times, the squamous epithelium of PEH can appear infiltrative, giving the illusion of well-differentiated SCC.⁵ However, absence of marked cellular atypia and abnormal mitotic activity should suggest otherwise. Thorough scrutiny for a concomitant infective process is necessary to avoid the overdiagnosis of SCC. Special stains for infectious agents such as periodic acid-Schiff and Grocott-Gomori methenamine-silver for fungal spores and Ziehl-Neelsen for acid-fast bacilli may reveal infectious organisms. Multilevel sections of deeper levels also may be essential to uncover sparse organisms.⁶

There is no standard treatment of chromomycosis. Some treatment options are available based on few open clinical studies and expert opinions. Systemic antifungals such as itraconazole or terbinafine most commonly are used with 15% to 80% cure rates.⁷ In invasive refractory cases, a combination of itraconazole and terbinafine has been employed as salvage therapy. Recently, the use of newer azoles such as posaconazole is favored due to its expanded-spectrum profile along with better pharmacodynamics and pharmacokinetic profile versus itraconazole. Physical methods such as cryotherapy, heat therapy, laser therapy, and photodynamic therapy frequently are practiced in conjunction with systemic antifungal therapy.⁸ Surgical procedures such as photocoagulation, Mohs micrographic surgery, and curettage sometimes are recommended for smaller well-defined lesions. Amputation, however, is rarely ever indicated, as there rarely is deep tissue involvement.²

Our case highlights the importance of clinicopathologic correlation in diagnosing squamous epithelial lesions. A high index of clinical suspicion and a wider list of differential diagnoses of verrucous plaques are necessary to minimize pitfalls in diagnosing lesions with squamous proliferation and therefore reduces the need for unnecessary interventions.

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.

To the Editor:

Vemurafenib, a selective BRAF inhibitor, is a chemotherapeutic agent used in the treatment of metastatic melanoma with BRAF mutations. It has been associated with various cutaneous side effects. We report a case of metastatic melanoma with acquired plantar hyperkeratosis secondary to vemurafenib therapy.

A 49-year-old man presented for evaluation of a pigmented plaque on the left pretibial region that had been enlarging over the last 2 months. The lesion had been diagnosed as folliculitis by his primary care physician 1 month prior to the current presentation and was being treated with oral antibiotics. The patient reported occasional bleeding from the lesion but denied other symptoms. Physical examination revealed a 1.4-cm pigmented plaque distributed over the left shin. Excisional biopsy was performed to rule out melanoma. Histopathology revealed well-circumscribed and symmetric proliferation of nested and single atypical melanocytes throughout all layers to the deep reticular dermis, confirming a clinical diagnosis of malignant melanoma. The lesion demonstrated angiolymphatic invasion, mitotic activity, and a Breslow depth of 2.5 mm. The patient underwent wide local excision with 3-cm margins and left inguinal sentinel lymph node biopsy; 2 of 14 lymph nodes were positive for melanoma. Positron emission tomography–computed tomography was negative for further metastatic disease. The patient underwent isolated limb perfusion with ipilimumab, but treatment was discontinued due to regional progression of multiple cutaneous metastases that were positive for the BRAF V600E mutation.

The patient was then started on vemurafenib therapy. Within 2 weeks, the patient reported various cutaneous symptoms, including morbilliform drug eruption covering approximately 70% of the body surface area that resolved with topical steroids and oral antihistamines, as well as the appearance of melanocytic nevi on the posterior neck, back, and abdomen. After 5 months of vemurafenib therapy, the patient began to develop hyperkeratosis of the bilateral soles of the feet (Figure). A diagnosis of acquired plantar hyperkeratosis secondary to vemurafenib therapy was made. Treatment with keratolytics was initiated and vemurafenib was not discontinued. The patient died approximately 1 year after therapy was started.

Metastatic melanoma is challenging to treat and continues to have a high mortality rate; however, newer chemotherapeutic agents targeting specific mutations found in melanoma, including the BRAF V600E mutation, are promising.

The US Food and Drug Administration first approved vemurafenib, a selective BRAF inhibitor, in 2011 for treatment of metastatic melanoma. Activating BRAF mutations have been detected in up to 60% of cutaneous melanomas.¹ In the majority of these mutations, valine (V) is inserted at codon 600 instead of glutamic acid (E); therefore, the mutation is named V600E.² In a phase 3 trial of 675 metastatic melanoma patients with positive V600E who were randomized to receive either vemurafenib or dacarbazine, the overall survival rate in the vemurafenib group improved by 84% versus 64% in the dacarbazine group at 6 months.³

Vemurafenib and other BRAF inhibitors have been associated with multiple cutaneous side effects, including rash, alopecia, squamous cell carcinoma, photosensitivity, evolution of existing nevi, and less commonly palmoplantar hyperkeratosis.^2-5 Constitutional symptoms including arthralgia, nausea, and fatigue also have been commonly reported.^2-5 In several large studies comprising 1138 patients, cutaneous side effects were seen in 92% to 95% of patients.^3,5 Adverse effects caused interruption or modification of therapy in 38% of patients.³

Palmoplantar keratoderma is a known side effect of vemurafenib therapy, but it is less commonly reported than other cutaneous adverse effects. It is believed that vemurafenib has the ability to paradoxically activate the mitogen-activated protein kinase pathway, leading to keratinocyte proliferation in cells without BRAF mutations.^6-8 In the phase 3 trial, approximately 23% to 30% of patients developed some form of hyperkeratosis.⁵ Comparatively, 64% of patients developed a rash and 23% developed cutaneous squamous cell carcinoma. Incidence of palmoplantar hyperkeratosis was similar in the vemurafenib and dabrafenib groups (6% vs 8%).^3,9 Development of keratoderma also has been associated with other multikinase inhibitors (eg, sorafenib, sunitinib).^10,11

In our case, the patient displayed multiple side effects while undergoing vemurafenib therapy. Within the first 2 weeks of therapy, he experienced a drug eruption that affected approximately 70% of the body surface area. The eruption resolved with topical steroids and oral antihistamines. The patient also noted the appearance of several new melanocytic nevi on the posterior neck as well as several evolving nevi on the back and abdomen. Five months into the treatment cycle, the patient began to develop hyperkeratosis on the bilateral plantar feet. Treatment consisted of keratolytics. Vemurafenib therapy was not discontinued secondary to any adverse effects.

Vemurafenib and other BRAF inhibitors are efficacious in the treatment of metastatic melanoma with V600E mutations. The use of these therapies is likely to continue and increase in the future. BRAF inhibitors have been associated with a variety of side effects, including palmoplantar hyperkeratosis. Awareness of and appropriate response to adverse reactions is essential to proper patient care and continuation of potentially life-extending therapies.

To the Editor:

Vemurafenib, a selective BRAF inhibitor, is a chemotherapeutic agent used in the treatment of metastatic melanoma with BRAF mutations. It has been associated with various cutaneous side effects. We report a case of metastatic melanoma with acquired plantar hyperkeratosis secondary to vemurafenib therapy.

A 49-year-old man presented for evaluation of a pigmented plaque on the left pretibial region that had been enlarging over the last 2 months. The lesion had been diagnosed as folliculitis by his primary care physician 1 month prior to the current presentation and was being treated with oral antibiotics. The patient reported occasional bleeding from the lesion but denied other symptoms. Physical examination revealed a 1.4-cm pigmented plaque distributed over the left shin. Excisional biopsy was performed to rule out melanoma. Histopathology revealed well-circumscribed and symmetric proliferation of nested and single atypical melanocytes throughout all layers to the deep reticular dermis, confirming a clinical diagnosis of malignant melanoma. The lesion demonstrated angiolymphatic invasion, mitotic activity, and a Breslow depth of 2.5 mm. The patient underwent wide local excision with 3-cm margins and left inguinal sentinel lymph node biopsy; 2 of 14 lymph nodes were positive for melanoma. Positron emission tomography–computed tomography was negative for further metastatic disease. The patient underwent isolated limb perfusion with ipilimumab, but treatment was discontinued due to regional progression of multiple cutaneous metastases that were positive for the BRAF V600E mutation.

The patient was then started on vemurafenib therapy. Within 2 weeks, the patient reported various cutaneous symptoms, including morbilliform drug eruption covering approximately 70% of the body surface area that resolved with topical steroids and oral antihistamines, as well as the appearance of melanocytic nevi on the posterior neck, back, and abdomen. After 5 months of vemurafenib therapy, the patient began to develop hyperkeratosis of the bilateral soles of the feet (Figure). A diagnosis of acquired plantar hyperkeratosis secondary to vemurafenib therapy was made. Treatment with keratolytics was initiated and vemurafenib was not discontinued. The patient died approximately 1 year after therapy was started.

Metastatic melanoma is challenging to treat and continues to have a high mortality rate; however, newer chemotherapeutic agents targeting specific mutations found in melanoma, including the BRAF V600E mutation, are promising.

The US Food and Drug Administration first approved vemurafenib, a selective BRAF inhibitor, in 2011 for treatment of metastatic melanoma. Activating BRAF mutations have been detected in up to 60% of cutaneous melanomas.¹ In the majority of these mutations, valine (V) is inserted at codon 600 instead of glutamic acid (E); therefore, the mutation is named V600E.² In a phase 3 trial of 675 metastatic melanoma patients with positive V600E who were randomized to receive either vemurafenib or dacarbazine, the overall survival rate in the vemurafenib group improved by 84% versus 64% in the dacarbazine group at 6 months.³

Vemurafenib and other BRAF inhibitors have been associated with multiple cutaneous side effects, including rash, alopecia, squamous cell carcinoma, photosensitivity, evolution of existing nevi, and less commonly palmoplantar hyperkeratosis.^2-5 Constitutional symptoms including arthralgia, nausea, and fatigue also have been commonly reported.^2-5 In several large studies comprising 1138 patients, cutaneous side effects were seen in 92% to 95% of patients.^3,5 Adverse effects caused interruption or modification of therapy in 38% of patients.³

Palmoplantar keratoderma is a known side effect of vemurafenib therapy, but it is less commonly reported than other cutaneous adverse effects. It is believed that vemurafenib has the ability to paradoxically activate the mitogen-activated protein kinase pathway, leading to keratinocyte proliferation in cells without BRAF mutations.^6-8 In the phase 3 trial, approximately 23% to 30% of patients developed some form of hyperkeratosis.⁵ Comparatively, 64% of patients developed a rash and 23% developed cutaneous squamous cell carcinoma. Incidence of palmoplantar hyperkeratosis was similar in the vemurafenib and dabrafenib groups (6% vs 8%).^3,9 Development of keratoderma also has been associated with other multikinase inhibitors (eg, sorafenib, sunitinib).^10,11

In our case, the patient displayed multiple side effects while undergoing vemurafenib therapy. Within the first 2 weeks of therapy, he experienced a drug eruption that affected approximately 70% of the body surface area. The eruption resolved with topical steroids and oral antihistamines. The patient also noted the appearance of several new melanocytic nevi on the posterior neck as well as several evolving nevi on the back and abdomen. Five months into the treatment cycle, the patient began to develop hyperkeratosis on the bilateral plantar feet. Treatment consisted of keratolytics. Vemurafenib therapy was not discontinued secondary to any adverse effects.

Vemurafenib and other BRAF inhibitors are efficacious in the treatment of metastatic melanoma with V600E mutations. The use of these therapies is likely to continue and increase in the future. BRAF inhibitors have been associated with a variety of side effects, including palmoplantar hyperkeratosis. Awareness of and appropriate response to adverse reactions is essential to proper patient care and continuation of potentially life-extending therapies.

To the Editor:

Vemurafenib, a selective BRAF inhibitor, is a chemotherapeutic agent used in the treatment of metastatic melanoma with BRAF mutations. It has been associated with various cutaneous side effects. We report a case of metastatic melanoma with acquired plantar hyperkeratosis secondary to vemurafenib therapy.

A 49-year-old man presented for evaluation of a pigmented plaque on the left pretibial region that had been enlarging over the last 2 months. The lesion had been diagnosed as folliculitis by his primary care physician 1 month prior to the current presentation and was being treated with oral antibiotics. The patient reported occasional bleeding from the lesion but denied other symptoms. Physical examination revealed a 1.4-cm pigmented plaque distributed over the left shin. Excisional biopsy was performed to rule out melanoma. Histopathology revealed well-circumscribed and symmetric proliferation of nested and single atypical melanocytes throughout all layers to the deep reticular dermis, confirming a clinical diagnosis of malignant melanoma. The lesion demonstrated angiolymphatic invasion, mitotic activity, and a Breslow depth of 2.5 mm. The patient underwent wide local excision with 3-cm margins and left inguinal sentinel lymph node biopsy; 2 of 14 lymph nodes were positive for melanoma. Positron emission tomography–computed tomography was negative for further metastatic disease. The patient underwent isolated limb perfusion with ipilimumab, but treatment was discontinued due to regional progression of multiple cutaneous metastases that were positive for the BRAF V600E mutation.

The patient was then started on vemurafenib therapy. Within 2 weeks, the patient reported various cutaneous symptoms, including morbilliform drug eruption covering approximately 70% of the body surface area that resolved with topical steroids and oral antihistamines, as well as the appearance of melanocytic nevi on the posterior neck, back, and abdomen. After 5 months of vemurafenib therapy, the patient began to develop hyperkeratosis of the bilateral soles of the feet (Figure). A diagnosis of acquired plantar hyperkeratosis secondary to vemurafenib therapy was made. Treatment with keratolytics was initiated and vemurafenib was not discontinued. The patient died approximately 1 year after therapy was started.

Metastatic melanoma is challenging to treat and continues to have a high mortality rate; however, newer chemotherapeutic agents targeting specific mutations found in melanoma, including the BRAF V600E mutation, are promising.

The US Food and Drug Administration first approved vemurafenib, a selective BRAF inhibitor, in 2011 for treatment of metastatic melanoma. Activating BRAF mutations have been detected in up to 60% of cutaneous melanomas.¹ In the majority of these mutations, valine (V) is inserted at codon 600 instead of glutamic acid (E); therefore, the mutation is named V600E.² In a phase 3 trial of 675 metastatic melanoma patients with positive V600E who were randomized to receive either vemurafenib or dacarbazine, the overall survival rate in the vemurafenib group improved by 84% versus 64% in the dacarbazine group at 6 months.³

Vemurafenib and other BRAF inhibitors have been associated with multiple cutaneous side effects, including rash, alopecia, squamous cell carcinoma, photosensitivity, evolution of existing nevi, and less commonly palmoplantar hyperkeratosis.^2-5 Constitutional symptoms including arthralgia, nausea, and fatigue also have been commonly reported.^2-5 In several large studies comprising 1138 patients, cutaneous side effects were seen in 92% to 95% of patients.^3,5 Adverse effects caused interruption or modification of therapy in 38% of patients.³

Palmoplantar keratoderma is a known side effect of vemurafenib therapy, but it is less commonly reported than other cutaneous adverse effects. It is believed that vemurafenib has the ability to paradoxically activate the mitogen-activated protein kinase pathway, leading to keratinocyte proliferation in cells without BRAF mutations.^6-8 In the phase 3 trial, approximately 23% to 30% of patients developed some form of hyperkeratosis.⁵ Comparatively, 64% of patients developed a rash and 23% developed cutaneous squamous cell carcinoma. Incidence of palmoplantar hyperkeratosis was similar in the vemurafenib and dabrafenib groups (6% vs 8%).^3,9 Development of keratoderma also has been associated with other multikinase inhibitors (eg, sorafenib, sunitinib).^10,11

In our case, the patient displayed multiple side effects while undergoing vemurafenib therapy. Within the first 2 weeks of therapy, he experienced a drug eruption that affected approximately 70% of the body surface area. The eruption resolved with topical steroids and oral antihistamines. The patient also noted the appearance of several new melanocytic nevi on the posterior neck as well as several evolving nevi on the back and abdomen. Five months into the treatment cycle, the patient began to develop hyperkeratosis on the bilateral plantar feet. Treatment consisted of keratolytics. Vemurafenib therapy was not discontinued secondary to any adverse effects.

Vemurafenib and other BRAF inhibitors are efficacious in the treatment of metastatic melanoma with V600E mutations. The use of these therapies is likely to continue and increase in the future. BRAF inhibitors have been associated with a variety of side effects, including palmoplantar hyperkeratosis. Awareness of and appropriate response to adverse reactions is essential to proper patient care and continuation of potentially life-extending therapies.

Cutaneous metastasis of internal malignancy is a relatively uncommon phenomenon, with an overall incidence of 5.3% in cancer patients.¹ Cutaneous involvement typically occurs late in the course of disease but can occasionally be the first extranodal sign of metastatic disease. Breast cancer has the highest rate of cutaneous metastasis, most often involving the chest wall¹; however, cutaneous metastasis to the acral sites is exceedingly rare. The hand is the site of 0.1% of all metastatic lesions, with only 10% of these being cutaneous lesions and the remaining 90% being osseous metastases.² Herein, we report a case of multiple cutaneous metastases to acral sites involving the palmar and plantar surfaces of the hands and feet.

Case Report

A 54-year-old black woman with a history of stage IV carcinoma of the breast was admitted to the university medical center with exquisitely painful cutaneous nodules on the hands and feet of 5 weeks’ duration that had started to cause difficulty with walking and daily activities. The patient reported that the breast carcinoma had initially been diagnosed in Nigeria 2 years prior, but she did not receive treatment until moving to the United States. She received a total of 4 cycles of chemotherapy with paclitaxel and bevacizumab, which was discontinued 6 weeks prior to admission due to pain in the lower extremities that was thought to be secondary to neuropathy. One week after discontinuation of chemotherapy, the patient reported increasing pain in the extremities and new-onset painful nodules on the hands and feet. Treatment with gabapentin as well as several courses of antibiotics failed to improve the condition.

She was admitted for symptomatic pain control and a dermatology consultation. Physical examination revealed multiple firm, tender, subcutaneous nodules on the volar surfaces of the soles, toes, palms, and fingertips (Figure 1). A nodule also was noted on the scalp. A punch biopsy of a nodule on the right fourth finger revealed a dermal carcinoma (Figure 2). On immunohistochemistry, the tumor stained positive for cytokeratin 5/6, cytokeratin 7, and gross cystic disease fluid protein 15. It did not demonstrate connection to the epidermis or adnexal structures. Although the tumor did not express estrogen or progesterone receptors, the findings were compatible with metastasis from the patient’s primary breast carcinoma with poor differentiation. A biopsy of the primary breast carcinoma was not available for review from Nigeria.

Comment

The majority of cases reporting acral cutaneous metastasis from internal malignancies are unilateral, involving only one extremity. Several hypotheses have been provided, including spread from localized trauma, which causes disruption of blood vessels and consequent extravasation and localization of tumor cells into the extravascular space.³ The distal extremities are particularly vulnerable to trauma, making this hypothesis plausible.

Considering the overall rarity of metastases to acral sites, it is interesting that our patient developed multiple distal nodules on both the hands and feet. The rapid onset of cutaneous nodules shortly after a course of chemotherapy led the team to consider the physiologic effects of paclitaxel and bevacizumab in the etiology of the acral cutaneous metastases. Karamouzis et al³ described a similar case of multiple cutaneous metastases with a bilateral acral distribution. This case also was associated with chemotherapy in the treatment of breast cancer. The authors proposed hand-foot syndrome, a chemotherapy-related eruption localized to acral skin, as a possible mechanism for hematogenous spread of malignant cells.³ The pathogenesis of hand-foot syndrome is not well understood, but the unique anatomy and physiology of acral skin including temperature gradients, rapidly dividing epidermal cells, absence of hair follicles and sebaceous glands, wide dermal papillae, and exposure to high pressures from carrying body weight and repetitive minor trauma may contribute to the localization of signs and symptoms.^3,4 Our case supports a chemotherapy-related etiology of acral cutaneous metastasis of a primary breast cancer; however, our patient did not have apparent signs or symptoms of hand-foot syndrome during the course of treatment. We propose that effects of bevacizumab on acral skin may have contributed to the development of our patient’s metastatic pattern.

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor A, has well-known vascular side effects. Unlike the inhibition of vascular endothelial growth factor A provided by the receptor tyrosine kinase inhibitors sorafenib and sunitinib, bevacizumab typically is not associated with hand-foot syndrome.⁵ However, several cases have been reported with chemotherapy-associated palmoplantar eruptions that resolved after withholding bevacizumab while continuing other chemotherapeutic agents, suggesting that bevacizumab-induced changes in acral skin contributed to the eruption.⁶ Specific factors that could contribute to acral metastasis in patients taking bevacizumab are endothelial dysfunction and capillary rarefaction of the acral skin, as well as hemorrhage, decreased wound healing, and changes in vascular permeability.^5,7

We present a rare case of acral cutaneous metastasis associated with bevacizumab, one of few reported cases associated with a taxane chemotherapeutic agent.³ More cases need to be identified and reported to establish a causative association, if indeed existent, between acral cutaneous metastasis of breast carcinoma and the use of bevacizumab as well as other chemotherapeutic drugs.

Cutaneous metastasis of internal malignancy is a relatively uncommon phenomenon, with an overall incidence of 5.3% in cancer patients.¹ Cutaneous involvement typically occurs late in the course of disease but can occasionally be the first extranodal sign of metastatic disease. Breast cancer has the highest rate of cutaneous metastasis, most often involving the chest wall¹; however, cutaneous metastasis to the acral sites is exceedingly rare. The hand is the site of 0.1% of all metastatic lesions, with only 10% of these being cutaneous lesions and the remaining 90% being osseous metastases.² Herein, we report a case of multiple cutaneous metastases to acral sites involving the palmar and plantar surfaces of the hands and feet.

Case Report

A 54-year-old black woman with a history of stage IV carcinoma of the breast was admitted to the university medical center with exquisitely painful cutaneous nodules on the hands and feet of 5 weeks’ duration that had started to cause difficulty with walking and daily activities. The patient reported that the breast carcinoma had initially been diagnosed in Nigeria 2 years prior, but she did not receive treatment until moving to the United States. She received a total of 4 cycles of chemotherapy with paclitaxel and bevacizumab, which was discontinued 6 weeks prior to admission due to pain in the lower extremities that was thought to be secondary to neuropathy. One week after discontinuation of chemotherapy, the patient reported increasing pain in the extremities and new-onset painful nodules on the hands and feet. Treatment with gabapentin as well as several courses of antibiotics failed to improve the condition.

She was admitted for symptomatic pain control and a dermatology consultation. Physical examination revealed multiple firm, tender, subcutaneous nodules on the volar surfaces of the soles, toes, palms, and fingertips (Figure 1). A nodule also was noted on the scalp. A punch biopsy of a nodule on the right fourth finger revealed a dermal carcinoma (Figure 2). On immunohistochemistry, the tumor stained positive for cytokeratin 5/6, cytokeratin 7, and gross cystic disease fluid protein 15. It did not demonstrate connection to the epidermis or adnexal structures. Although the tumor did not express estrogen or progesterone receptors, the findings were compatible with metastasis from the patient’s primary breast carcinoma with poor differentiation. A biopsy of the primary breast carcinoma was not available for review from Nigeria.

Comment

The majority of cases reporting acral cutaneous metastasis from internal malignancies are unilateral, involving only one extremity. Several hypotheses have been provided, including spread from localized trauma, which causes disruption of blood vessels and consequent extravasation and localization of tumor cells into the extravascular space.³ The distal extremities are particularly vulnerable to trauma, making this hypothesis plausible.

Considering the overall rarity of metastases to acral sites, it is interesting that our patient developed multiple distal nodules on both the hands and feet. The rapid onset of cutaneous nodules shortly after a course of chemotherapy led the team to consider the physiologic effects of paclitaxel and bevacizumab in the etiology of the acral cutaneous metastases. Karamouzis et al³ described a similar case of multiple cutaneous metastases with a bilateral acral distribution. This case also was associated with chemotherapy in the treatment of breast cancer. The authors proposed hand-foot syndrome, a chemotherapy-related eruption localized to acral skin, as a possible mechanism for hematogenous spread of malignant cells.³ The pathogenesis of hand-foot syndrome is not well understood, but the unique anatomy and physiology of acral skin including temperature gradients, rapidly dividing epidermal cells, absence of hair follicles and sebaceous glands, wide dermal papillae, and exposure to high pressures from carrying body weight and repetitive minor trauma may contribute to the localization of signs and symptoms.^3,4 Our case supports a chemotherapy-related etiology of acral cutaneous metastasis of a primary breast cancer; however, our patient did not have apparent signs or symptoms of hand-foot syndrome during the course of treatment. We propose that effects of bevacizumab on acral skin may have contributed to the development of our patient’s metastatic pattern.

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor A, has well-known vascular side effects. Unlike the inhibition of vascular endothelial growth factor A provided by the receptor tyrosine kinase inhibitors sorafenib and sunitinib, bevacizumab typically is not associated with hand-foot syndrome.⁵ However, several cases have been reported with chemotherapy-associated palmoplantar eruptions that resolved after withholding bevacizumab while continuing other chemotherapeutic agents, suggesting that bevacizumab-induced changes in acral skin contributed to the eruption.⁶ Specific factors that could contribute to acral metastasis in patients taking bevacizumab are endothelial dysfunction and capillary rarefaction of the acral skin, as well as hemorrhage, decreased wound healing, and changes in vascular permeability.^5,7

We present a rare case of acral cutaneous metastasis associated with bevacizumab, one of few reported cases associated with a taxane chemotherapeutic agent.³ More cases need to be identified and reported to establish a causative association, if indeed existent, between acral cutaneous metastasis of breast carcinoma and the use of bevacizumab as well as other chemotherapeutic drugs.

Cutaneous metastasis of internal malignancy is a relatively uncommon phenomenon, with an overall incidence of 5.3% in cancer patients.¹ Cutaneous involvement typically occurs late in the course of disease but can occasionally be the first extranodal sign of metastatic disease. Breast cancer has the highest rate of cutaneous metastasis, most often involving the chest wall¹; however, cutaneous metastasis to the acral sites is exceedingly rare. The hand is the site of 0.1% of all metastatic lesions, with only 10% of these being cutaneous lesions and the remaining 90% being osseous metastases.² Herein, we report a case of multiple cutaneous metastases to acral sites involving the palmar and plantar surfaces of the hands and feet.

Case Report

A 54-year-old black woman with a history of stage IV carcinoma of the breast was admitted to the university medical center with exquisitely painful cutaneous nodules on the hands and feet of 5 weeks’ duration that had started to cause difficulty with walking and daily activities. The patient reported that the breast carcinoma had initially been diagnosed in Nigeria 2 years prior, but she did not receive treatment until moving to the United States. She received a total of 4 cycles of chemotherapy with paclitaxel and bevacizumab, which was discontinued 6 weeks prior to admission due to pain in the lower extremities that was thought to be secondary to neuropathy. One week after discontinuation of chemotherapy, the patient reported increasing pain in the extremities and new-onset painful nodules on the hands and feet. Treatment with gabapentin as well as several courses of antibiotics failed to improve the condition.

She was admitted for symptomatic pain control and a dermatology consultation. Physical examination revealed multiple firm, tender, subcutaneous nodules on the volar surfaces of the soles, toes, palms, and fingertips (Figure 1). A nodule also was noted on the scalp. A punch biopsy of a nodule on the right fourth finger revealed a dermal carcinoma (Figure 2). On immunohistochemistry, the tumor stained positive for cytokeratin 5/6, cytokeratin 7, and gross cystic disease fluid protein 15. It did not demonstrate connection to the epidermis or adnexal structures. Although the tumor did not express estrogen or progesterone receptors, the findings were compatible with metastasis from the patient’s primary breast carcinoma with poor differentiation. A biopsy of the primary breast carcinoma was not available for review from Nigeria.

Comment

The majority of cases reporting acral cutaneous metastasis from internal malignancies are unilateral, involving only one extremity. Several hypotheses have been provided, including spread from localized trauma, which causes disruption of blood vessels and consequent extravasation and localization of tumor cells into the extravascular space.³ The distal extremities are particularly vulnerable to trauma, making this hypothesis plausible.

Considering the overall rarity of metastases to acral sites, it is interesting that our patient developed multiple distal nodules on both the hands and feet. The rapid onset of cutaneous nodules shortly after a course of chemotherapy led the team to consider the physiologic effects of paclitaxel and bevacizumab in the etiology of the acral cutaneous metastases. Karamouzis et al³ described a similar case of multiple cutaneous metastases with a bilateral acral distribution. This case also was associated with chemotherapy in the treatment of breast cancer. The authors proposed hand-foot syndrome, a chemotherapy-related eruption localized to acral skin, as a possible mechanism for hematogenous spread of malignant cells.³ The pathogenesis of hand-foot syndrome is not well understood, but the unique anatomy and physiology of acral skin including temperature gradients, rapidly dividing epidermal cells, absence of hair follicles and sebaceous glands, wide dermal papillae, and exposure to high pressures from carrying body weight and repetitive minor trauma may contribute to the localization of signs and symptoms.^3,4 Our case supports a chemotherapy-related etiology of acral cutaneous metastasis of a primary breast cancer; however, our patient did not have apparent signs or symptoms of hand-foot syndrome during the course of treatment. We propose that effects of bevacizumab on acral skin may have contributed to the development of our patient’s metastatic pattern.

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor A, has well-known vascular side effects. Unlike the inhibition of vascular endothelial growth factor A provided by the receptor tyrosine kinase inhibitors sorafenib and sunitinib, bevacizumab typically is not associated with hand-foot syndrome.⁵ However, several cases have been reported with chemotherapy-associated palmoplantar eruptions that resolved after withholding bevacizumab while continuing other chemotherapeutic agents, suggesting that bevacizumab-induced changes in acral skin contributed to the eruption.⁶ Specific factors that could contribute to acral metastasis in patients taking bevacizumab are endothelial dysfunction and capillary rarefaction of the acral skin, as well as hemorrhage, decreased wound healing, and changes in vascular permeability.^5,7

We present a rare case of acral cutaneous metastasis associated with bevacizumab, one of few reported cases associated with a taxane chemotherapeutic agent.³ More cases need to be identified and reported to establish a causative association, if indeed existent, between acral cutaneous metastasis of breast carcinoma and the use of bevacizumab as well as other chemotherapeutic drugs.

The Diagnosis: Herpes Simplex Virus Infection

Viral culture of the ulcer was positive for herpes simplex virus type 2 (HHV-2). Bacterial culture grew enteric flora. The patient was started on intravenous acyclovir 5 mg/kg every 8 hours for 7 days and then transitioned to oral acyclovir for chronic suppressive therapy. One month later, there was near-complete reepithelialization with 2 remaining 1-cm shallow ulcers. The verrucous lesions had dried up and were flaking off (Figure). At 6-month follow-up, the ulcers and verrucous lesions had completely resolved.

Herpes simplex virus type 2 is the most common cause of genital and perianal ulcers in immunocompromised individuals.¹ Patients classically present with painful grouped vesicles followed by painful superficial ulcers that may rapidly progress to extensive confluent ulceration. A hypertrophic variant of genital herpes characterized by anogenital verrucous lesions, similar to condyloma acuminata, also can be seen in immunocompromised individuals.² This form has almost exclusively been observed in patients with human immunodeficiency virus and may occur in isolation or together with the ulcerative form.^1-5 A case of vegetative HHV infection of the genital area in a patient with common variable immunodeficiency has been reported.⁶ Verrucous lesions of the mouth secondary to HHV have been observed in Hodgkin lymphoma, acute myelogenous leukemia, and individuals on immunosuppressive medications.^7-10

Perianal involvement of Crohn disease typically presents with fistulas, ulcers, abscesses, strictures, and skin tags in some cases. Invasive squamous cell carcinoma may arise within a chronic ulcer of the anogenital area or may itself manifest as an ulcer or anal fissure. Perianal ulcerative skin tuberculosis has been reported in the literature as a rare manifestation of extrapulmonary tuberculosis and should be considered in a patient with an appropriate clinical history. Pyoderma gangrenosum classically pre-sents as a large ulcer with irregular rolled borders, though a rare variant of vegetative pyoderma gangrenosum may manifest as a nodular or verrucous plaque.

Studies to diagnose HHV include viral cell culture, HHV polymerase chain reaction testing, HHV serology, and direct fluorescent antibody testing. Skin biopsy may be necessary to rule out underlying malignancy. Treatment of perianal HHV infection includes acyclovir, valacyclovir, or famciclovir.^1,5,6 Hypertrophic lesions often are refractory to first-line antiviral therapy and may require surgical resection or treatment with alternative medications such as imiquimod, a topical immunomodulator.^3,5,6,11

The Diagnosis: Herpes Simplex Virus Infection

Viral culture of the ulcer was positive for herpes simplex virus type 2 (HHV-2). Bacterial culture grew enteric flora. The patient was started on intravenous acyclovir 5 mg/kg every 8 hours for 7 days and then transitioned to oral acyclovir for chronic suppressive therapy. One month later, there was near-complete reepithelialization with 2 remaining 1-cm shallow ulcers. The verrucous lesions had dried up and were flaking off (Figure). At 6-month follow-up, the ulcers and verrucous lesions had completely resolved.

Herpes simplex virus type 2 is the most common cause of genital and perianal ulcers in immunocompromised individuals.¹ Patients classically present with painful grouped vesicles followed by painful superficial ulcers that may rapidly progress to extensive confluent ulceration. A hypertrophic variant of genital herpes characterized by anogenital verrucous lesions, similar to condyloma acuminata, also can be seen in immunocompromised individuals.² This form has almost exclusively been observed in patients with human immunodeficiency virus and may occur in isolation or together with the ulcerative form.^1-5 A case of vegetative HHV infection of the genital area in a patient with common variable immunodeficiency has been reported.⁶ Verrucous lesions of the mouth secondary to HHV have been observed in Hodgkin lymphoma, acute myelogenous leukemia, and individuals on immunosuppressive medications.^7-10

Perianal involvement of Crohn disease typically presents with fistulas, ulcers, abscesses, strictures, and skin tags in some cases. Invasive squamous cell carcinoma may arise within a chronic ulcer of the anogenital area or may itself manifest as an ulcer or anal fissure. Perianal ulcerative skin tuberculosis has been reported in the literature as a rare manifestation of extrapulmonary tuberculosis and should be considered in a patient with an appropriate clinical history. Pyoderma gangrenosum classically pre-sents as a large ulcer with irregular rolled borders, though a rare variant of vegetative pyoderma gangrenosum may manifest as a nodular or verrucous plaque.

Studies to diagnose HHV include viral cell culture, HHV polymerase chain reaction testing, HHV serology, and direct fluorescent antibody testing. Skin biopsy may be necessary to rule out underlying malignancy. Treatment of perianal HHV infection includes acyclovir, valacyclovir, or famciclovir.^1,5,6 Hypertrophic lesions often are refractory to first-line antiviral therapy and may require surgical resection or treatment with alternative medications such as imiquimod, a topical immunomodulator.^3,5,6,11

The Diagnosis: Herpes Simplex Virus Infection

Viral culture of the ulcer was positive for herpes simplex virus type 2 (HHV-2). Bacterial culture grew enteric flora. The patient was started on intravenous acyclovir 5 mg/kg every 8 hours for 7 days and then transitioned to oral acyclovir for chronic suppressive therapy. One month later, there was near-complete reepithelialization with 2 remaining 1-cm shallow ulcers. The verrucous lesions had dried up and were flaking off (Figure). At 6-month follow-up, the ulcers and verrucous lesions had completely resolved.

Herpes simplex virus type 2 is the most common cause of genital and perianal ulcers in immunocompromised individuals.¹ Patients classically present with painful grouped vesicles followed by painful superficial ulcers that may rapidly progress to extensive confluent ulceration. A hypertrophic variant of genital herpes characterized by anogenital verrucous lesions, similar to condyloma acuminata, also can be seen in immunocompromised individuals.² This form has almost exclusively been observed in patients with human immunodeficiency virus and may occur in isolation or together with the ulcerative form.^1-5 A case of vegetative HHV infection of the genital area in a patient with common variable immunodeficiency has been reported.⁶ Verrucous lesions of the mouth secondary to HHV have been observed in Hodgkin lymphoma, acute myelogenous leukemia, and individuals on immunosuppressive medications.^7-10

Perianal involvement of Crohn disease typically presents with fistulas, ulcers, abscesses, strictures, and skin tags in some cases. Invasive squamous cell carcinoma may arise within a chronic ulcer of the anogenital area or may itself manifest as an ulcer or anal fissure. Perianal ulcerative skin tuberculosis has been reported in the literature as a rare manifestation of extrapulmonary tuberculosis and should be considered in a patient with an appropriate clinical history. Pyoderma gangrenosum classically pre-sents as a large ulcer with irregular rolled borders, though a rare variant of vegetative pyoderma gangrenosum may manifest as a nodular or verrucous plaque.

Studies to diagnose HHV include viral cell culture, HHV polymerase chain reaction testing, HHV serology, and direct fluorescent antibody testing. Skin biopsy may be necessary to rule out underlying malignancy. Treatment of perianal HHV infection includes acyclovir, valacyclovir, or famciclovir.^1,5,6 Hypertrophic lesions often are refractory to first-line antiviral therapy and may require surgical resection or treatment with alternative medications such as imiquimod, a topical immunomodulator.^3,5,6,11