Dermatopathology

Intravascular large B-cell lymphoma (IVBCL) is an exceedingly rare aggressive form of non-Hodgkin lymphoma with tumor cells growing selectively in vascular lumina.¹ The annual incidence of IVBCL is fewer than 0.5 cases per 1,000,000 individuals worldwide.² Only about 500 known cases of IVBCL have been recorded in the literature,³ and it accounts for less than 1% of all lymphomas. It generally affects middle-aged to elderly individuals, with an average age at diagnosis of 70 years.² It has a predilection for men and commonly develops in individuals who are immunosuppressed.^3,4

Multiple variants of IVBCL have been described in the literature, with central nervous system and cutaneous involvement being the most classic findings.⁵ Bone marrow involvement with hepatosplenomegaly also has been noted in the literature.^6,7 Diagnosis of IVBCL and its variants requires a high index of suspicion, as the clinical manifestations and tissues involved typically are nonspecific and highly variable. Even in the classic variant of IVBCL, skin involvement is only reported in approximately half of cases.³ When present, cutaneous manifestations can range from nodules and violaceous plaques to induration and telangiectasias.³ Lymphadenopathy and lymphoma (leukemic) cells are not seen on a peripheral blood smear.^2,8,9

The lack of lymphadenopathy or identifiable leukemic cells in the peripheral blood presents a diagnostic dilemma, as sufficient information for accurate diagnosis must be obtained while minimizing invasive procedures and resource expenditure. Because IVBCL cells can reside in the vascular lumina of various organs, numerous biopsy sites have been proposed for diagnosis of lymphoma, including the bone marrow, skin, prostate, adrenal gland, brain, liver, and kidneys.¹⁰ While some studies have reported that the optimal diagnostic site is the bone marrow, skin biopsies are more routinely carried out, as they represent a convenient and cost-effective alternative to other more invasive techniques.^6,7,10 Studies have shown biopsy sensitivity values ranging from 77.8% to 83.3% for detection of IVBCL in normal-appearing skin, which is comparable to the sensitivities of a bone marrow biopsy.^7,8 Although skin biopsy of random sites has shown diagnostic efficacy, some studies have proposed that biopsies taken from hemangiomas and other hypervascular lesions can further improve diagnostic yield, as lymphoma cells often are present in capillaries of subcutaneous adipose tissue.^6,10,11 However, no obvious clinicopathologic differences were observed between IVBCL with and without involvement of a cutaneous hemangioma.¹¹

The purpose of this study was to determine the diagnostic efficacy of skin biopsies for detecting IVBCL at various body sites and to establish whether biopsies from hemangiomas yield higher diagnostic value.

Methods

A 66-year-old man recently died at our institution secondary to IVBCL. His disease course was characterized by multiple hospital admissions in a 6-month period for fever of unknown origin and tachycardia unresponsive to broad-spectrum antibiotics and systemic steroids. The patient declined over the course of 3 to 4 weeks with findings suggestive of lymphoma and tumor lysis syndrome, and he eventually developed shock, hypoxic respiratory failure, and acute renal failure. As imaging studies and examinations had not shown lymphadenopathy, bone marrow biopsy was performed, and dermatology was consulted to perform skin biopsies to evaluate for IVBCL. Both bone marrow biopsies and random skin biopsies from the abdomen showed large and atypical CD20+ B cells within select vascular lumina (Figure). No extravascular lymphoma cells were seen. Based on the bone marrow and skin biopsies, a diagnosis of IVBCL was made. Unfortunately, no progress was made clinically, and the patient was transitioned to comfort measures. Upon the patient’s death, his family expressed interest in participating in IVBCL research and agreed to a limited autopsy consisting of numerous skin biopsies to evaluate different body sites and biopsy types (normal skin vs hemangiomas) to ascertain whether diagnostic yield could be increased by performing selective biopsies of hemangiomas if IVBCL was suspected.

Twenty-four postmortem 4-mm punch biopsies containing subcutaneous adipose tissue were taken within 24 hours of the death of the patient before embalming. The biopsies were taken from all regions of the body except the head and neck for cosmetic preservation of the decedent. Eighteen of the biopsies were taken from random sites of normal-appearing skin; the remaining 6 were taken from clinically identifiable cherry hemangiomas (5 on the trunk and 1 on the thigh). There was a variable degree of livor mortis in the dependent areas of the body, which was included in the random biopsies from the back to ensure any pooling of dependent blood would not alter the findings.

A histopathologic examination by a board-certified dermatopathologist (M.P.) on a single hematoxylin-eosin–stained level was performed to evaluate each biopsy for superficial involvement and deep involvement by IVBCL. Superficial involvement was defined as dermal involvement at or above the level of the eccrine sweat glands; deep involvement was defined as dermal involvement beneath the eccrine sweat glands and all subcutaneous fat present. Skin and bone marrow biopsies used to make the original diagnosis prior to the patient’s death were reviewed, including CD20 immunohistochemistry for morphologic comparison to the study slides. Involvement was graded as 0 to 3+ (eTable).

Results

Results from all 24 biopsies are shown in the eTable. Twenty-two (91.7%) biopsies showed at least focal involvement by IVBCL. Nine (37.5%) biopsies showed more deep vs superficial involvement of the same site. On average, the 6 biopsies from clinically detected hemangiomas showed more involvement by IVBCL than the random biopsies (eFigures 1 and 2A). The superficial involvement of skin with a hemangioma showed an average score of 2.33 v 0.78 when compared with the superficial aspect of the random biopsies; the deep involvement of skin with a hemangioma showed an average score of 2.67 vs 1.16 when compared with the deep aspect of the random biopsies (eFigure 2B).

Comment

Intravascular large B-cell lymphoma is an aggressive malignancy that traditionally is difficult to diagnose. Many efforts have been made to improve detection and early diagnosis. As cutaneous involvement is common and sometimes the only sign of disease, dermatologists may be called upon to evaluate and biopsy patients with this suspected diagnosis. The purpose of our study was to improve diagnostic efficacy by methodically performing numerous biopsies and assessing the level of involvement of the superficial and deep skin as well as involvement of hemangiomas. The goal of this meticulous approach was to identify the highest-yield areas for biopsy with minimal impact on the patient. Our results showed that random skin biopsies are an effective way to identify IVBCL. Twenty-two (91.7%) biopsies contained at least focal lymphoma cells. Although the 2 biopsies that showed no tumor cells at all happened to both be from the left arm, this is believed to be coincidental. No discernable pattern was identified regarding involvement and anatomic region. Even though 20 (83.3%) biopsies showed superficial involvement, deep biopsy is essential, as 9 (37.5%) biopsies showed increased deep involvement compared to superficial involvement. Therefore, a deep punch biopsy is essential for maximum sensitivity.

Hemangiomas provide a potential target that could increase the sensitivity of a biopsy in the absence of clinical findings, when the disease in question is exclusively intravascular. The data gathered in this study support this idea, as biopsies from hemangiomas showed increased involvement compared to random biopsies, both superficially and deep (2.33 vs 0.78 and 2.67 vs 1.16, respectively). Interestingly, the hemangioma biopsy sites showed increased deep and superficial involvement, despite these typical cherry hemangiomas only involving the superficial dermis. One possible explanation for this is that the hemangiomas have larger-caliber feeder vessels with increased blood flow beneath them. It would then follow that this increased vasculature would increase the chances of identifying intravascular lymphoma cells. This finding further accentuates the need for a deep punch biopsy containing subcutaneous fat. 

Completing the study in the setting of an autopsy provided the advantage of being able to take numerous biopsies without increased harm to the patient. This extensive set of biopsies would not be reasonable to complete on a living patient. This study also has limitations. Although this patient did fall within the typical demographics for patients with IVBCL, the data were still limited to 1 patient. This autopsy format (on a patient whose cause of death was indeed IVBCL) also implies terminal disease, which may mean the patient had a larger disease burden than a living patient who would typically be biopsied. Although this increased disease burden may have increased the sensitivity of finding IVBCL in the biopsies of this study, this further emphasizes the importance of trying to determine any factors that could increase sensitivity in a living patient with a lower disease burden.

Conclusion

Skin biopsies can provide a sensitive, low-cost, and low-morbidity method to assess a patient for IVBCL. Though random skin biopsies can yield valuable information, deep, 4-mm punch biopsies of clinically identifiable hemangiomas may provide the highest sensitivity for IVBCL.

Intravascular large B-cell lymphoma (IVBCL) is an exceedingly rare aggressive form of non-Hodgkin lymphoma with tumor cells growing selectively in vascular lumina.¹ The annual incidence of IVBCL is fewer than 0.5 cases per 1,000,000 individuals worldwide.² Only about 500 known cases of IVBCL have been recorded in the literature,³ and it accounts for less than 1% of all lymphomas. It generally affects middle-aged to elderly individuals, with an average age at diagnosis of 70 years.² It has a predilection for men and commonly develops in individuals who are immunosuppressed.^3,4

Multiple variants of IVBCL have been described in the literature, with central nervous system and cutaneous involvement being the most classic findings.⁵ Bone marrow involvement with hepatosplenomegaly also has been noted in the literature.^6,7 Diagnosis of IVBCL and its variants requires a high index of suspicion, as the clinical manifestations and tissues involved typically are nonspecific and highly variable. Even in the classic variant of IVBCL, skin involvement is only reported in approximately half of cases.³ When present, cutaneous manifestations can range from nodules and violaceous plaques to induration and telangiectasias.³ Lymphadenopathy and lymphoma (leukemic) cells are not seen on a peripheral blood smear.^2,8,9

The lack of lymphadenopathy or identifiable leukemic cells in the peripheral blood presents a diagnostic dilemma, as sufficient information for accurate diagnosis must be obtained while minimizing invasive procedures and resource expenditure. Because IVBCL cells can reside in the vascular lumina of various organs, numerous biopsy sites have been proposed for diagnosis of lymphoma, including the bone marrow, skin, prostate, adrenal gland, brain, liver, and kidneys.¹⁰ While some studies have reported that the optimal diagnostic site is the bone marrow, skin biopsies are more routinely carried out, as they represent a convenient and cost-effective alternative to other more invasive techniques.^6,7,10 Studies have shown biopsy sensitivity values ranging from 77.8% to 83.3% for detection of IVBCL in normal-appearing skin, which is comparable to the sensitivities of a bone marrow biopsy.^7,8 Although skin biopsy of random sites has shown diagnostic efficacy, some studies have proposed that biopsies taken from hemangiomas and other hypervascular lesions can further improve diagnostic yield, as lymphoma cells often are present in capillaries of subcutaneous adipose tissue.^6,10,11 However, no obvious clinicopathologic differences were observed between IVBCL with and without involvement of a cutaneous hemangioma.¹¹

The purpose of this study was to determine the diagnostic efficacy of skin biopsies for detecting IVBCL at various body sites and to establish whether biopsies from hemangiomas yield higher diagnostic value.

Methods

A 66-year-old man recently died at our institution secondary to IVBCL. His disease course was characterized by multiple hospital admissions in a 6-month period for fever of unknown origin and tachycardia unresponsive to broad-spectrum antibiotics and systemic steroids. The patient declined over the course of 3 to 4 weeks with findings suggestive of lymphoma and tumor lysis syndrome, and he eventually developed shock, hypoxic respiratory failure, and acute renal failure. As imaging studies and examinations had not shown lymphadenopathy, bone marrow biopsy was performed, and dermatology was consulted to perform skin biopsies to evaluate for IVBCL. Both bone marrow biopsies and random skin biopsies from the abdomen showed large and atypical CD20+ B cells within select vascular lumina (Figure). No extravascular lymphoma cells were seen. Based on the bone marrow and skin biopsies, a diagnosis of IVBCL was made. Unfortunately, no progress was made clinically, and the patient was transitioned to comfort measures. Upon the patient’s death, his family expressed interest in participating in IVBCL research and agreed to a limited autopsy consisting of numerous skin biopsies to evaluate different body sites and biopsy types (normal skin vs hemangiomas) to ascertain whether diagnostic yield could be increased by performing selective biopsies of hemangiomas if IVBCL was suspected.

Twenty-four postmortem 4-mm punch biopsies containing subcutaneous adipose tissue were taken within 24 hours of the death of the patient before embalming. The biopsies were taken from all regions of the body except the head and neck for cosmetic preservation of the decedent. Eighteen of the biopsies were taken from random sites of normal-appearing skin; the remaining 6 were taken from clinically identifiable cherry hemangiomas (5 on the trunk and 1 on the thigh). There was a variable degree of livor mortis in the dependent areas of the body, which was included in the random biopsies from the back to ensure any pooling of dependent blood would not alter the findings.

A histopathologic examination by a board-certified dermatopathologist (M.P.) on a single hematoxylin-eosin–stained level was performed to evaluate each biopsy for superficial involvement and deep involvement by IVBCL. Superficial involvement was defined as dermal involvement at or above the level of the eccrine sweat glands; deep involvement was defined as dermal involvement beneath the eccrine sweat glands and all subcutaneous fat present. Skin and bone marrow biopsies used to make the original diagnosis prior to the patient’s death were reviewed, including CD20 immunohistochemistry for morphologic comparison to the study slides. Involvement was graded as 0 to 3+ (eTable).

Results

Results from all 24 biopsies are shown in the eTable. Twenty-two (91.7%) biopsies showed at least focal involvement by IVBCL. Nine (37.5%) biopsies showed more deep vs superficial involvement of the same site. On average, the 6 biopsies from clinically detected hemangiomas showed more involvement by IVBCL than the random biopsies (eFigures 1 and 2A). The superficial involvement of skin with a hemangioma showed an average score of 2.33 v 0.78 when compared with the superficial aspect of the random biopsies; the deep involvement of skin with a hemangioma showed an average score of 2.67 vs 1.16 when compared with the deep aspect of the random biopsies (eFigure 2B).

Comment

Intravascular large B-cell lymphoma is an aggressive malignancy that traditionally is difficult to diagnose. Many efforts have been made to improve detection and early diagnosis. As cutaneous involvement is common and sometimes the only sign of disease, dermatologists may be called upon to evaluate and biopsy patients with this suspected diagnosis. The purpose of our study was to improve diagnostic efficacy by methodically performing numerous biopsies and assessing the level of involvement of the superficial and deep skin as well as involvement of hemangiomas. The goal of this meticulous approach was to identify the highest-yield areas for biopsy with minimal impact on the patient. Our results showed that random skin biopsies are an effective way to identify IVBCL. Twenty-two (91.7%) biopsies contained at least focal lymphoma cells. Although the 2 biopsies that showed no tumor cells at all happened to both be from the left arm, this is believed to be coincidental. No discernable pattern was identified regarding involvement and anatomic region. Even though 20 (83.3%) biopsies showed superficial involvement, deep biopsy is essential, as 9 (37.5%) biopsies showed increased deep involvement compared to superficial involvement. Therefore, a deep punch biopsy is essential for maximum sensitivity.

Hemangiomas provide a potential target that could increase the sensitivity of a biopsy in the absence of clinical findings, when the disease in question is exclusively intravascular. The data gathered in this study support this idea, as biopsies from hemangiomas showed increased involvement compared to random biopsies, both superficially and deep (2.33 vs 0.78 and 2.67 vs 1.16, respectively). Interestingly, the hemangioma biopsy sites showed increased deep and superficial involvement, despite these typical cherry hemangiomas only involving the superficial dermis. One possible explanation for this is that the hemangiomas have larger-caliber feeder vessels with increased blood flow beneath them. It would then follow that this increased vasculature would increase the chances of identifying intravascular lymphoma cells. This finding further accentuates the need for a deep punch biopsy containing subcutaneous fat. 

Completing the study in the setting of an autopsy provided the advantage of being able to take numerous biopsies without increased harm to the patient. This extensive set of biopsies would not be reasonable to complete on a living patient. This study also has limitations. Although this patient did fall within the typical demographics for patients with IVBCL, the data were still limited to 1 patient. This autopsy format (on a patient whose cause of death was indeed IVBCL) also implies terminal disease, which may mean the patient had a larger disease burden than a living patient who would typically be biopsied. Although this increased disease burden may have increased the sensitivity of finding IVBCL in the biopsies of this study, this further emphasizes the importance of trying to determine any factors that could increase sensitivity in a living patient with a lower disease burden.

Conclusion

Skin biopsies can provide a sensitive, low-cost, and low-morbidity method to assess a patient for IVBCL. Though random skin biopsies can yield valuable information, deep, 4-mm punch biopsies of clinically identifiable hemangiomas may provide the highest sensitivity for IVBCL.

Intravascular large B-cell lymphoma (IVBCL) is an exceedingly rare aggressive form of non-Hodgkin lymphoma with tumor cells growing selectively in vascular lumina.¹ The annual incidence of IVBCL is fewer than 0.5 cases per 1,000,000 individuals worldwide.² Only about 500 known cases of IVBCL have been recorded in the literature,³ and it accounts for less than 1% of all lymphomas. It generally affects middle-aged to elderly individuals, with an average age at diagnosis of 70 years.² It has a predilection for men and commonly develops in individuals who are immunosuppressed.^3,4

Multiple variants of IVBCL have been described in the literature, with central nervous system and cutaneous involvement being the most classic findings.⁵ Bone marrow involvement with hepatosplenomegaly also has been noted in the literature.^6,7 Diagnosis of IVBCL and its variants requires a high index of suspicion, as the clinical manifestations and tissues involved typically are nonspecific and highly variable. Even in the classic variant of IVBCL, skin involvement is only reported in approximately half of cases.³ When present, cutaneous manifestations can range from nodules and violaceous plaques to induration and telangiectasias.³ Lymphadenopathy and lymphoma (leukemic) cells are not seen on a peripheral blood smear.^2,8,9

The lack of lymphadenopathy or identifiable leukemic cells in the peripheral blood presents a diagnostic dilemma, as sufficient information for accurate diagnosis must be obtained while minimizing invasive procedures and resource expenditure. Because IVBCL cells can reside in the vascular lumina of various organs, numerous biopsy sites have been proposed for diagnosis of lymphoma, including the bone marrow, skin, prostate, adrenal gland, brain, liver, and kidneys.¹⁰ While some studies have reported that the optimal diagnostic site is the bone marrow, skin biopsies are more routinely carried out, as they represent a convenient and cost-effective alternative to other more invasive techniques.^6,7,10 Studies have shown biopsy sensitivity values ranging from 77.8% to 83.3% for detection of IVBCL in normal-appearing skin, which is comparable to the sensitivities of a bone marrow biopsy.^7,8 Although skin biopsy of random sites has shown diagnostic efficacy, some studies have proposed that biopsies taken from hemangiomas and other hypervascular lesions can further improve diagnostic yield, as lymphoma cells often are present in capillaries of subcutaneous adipose tissue.^6,10,11 However, no obvious clinicopathologic differences were observed between IVBCL with and without involvement of a cutaneous hemangioma.¹¹

The purpose of this study was to determine the diagnostic efficacy of skin biopsies for detecting IVBCL at various body sites and to establish whether biopsies from hemangiomas yield higher diagnostic value.

Methods

A 66-year-old man recently died at our institution secondary to IVBCL. His disease course was characterized by multiple hospital admissions in a 6-month period for fever of unknown origin and tachycardia unresponsive to broad-spectrum antibiotics and systemic steroids. The patient declined over the course of 3 to 4 weeks with findings suggestive of lymphoma and tumor lysis syndrome, and he eventually developed shock, hypoxic respiratory failure, and acute renal failure. As imaging studies and examinations had not shown lymphadenopathy, bone marrow biopsy was performed, and dermatology was consulted to perform skin biopsies to evaluate for IVBCL. Both bone marrow biopsies and random skin biopsies from the abdomen showed large and atypical CD20+ B cells within select vascular lumina (Figure). No extravascular lymphoma cells were seen. Based on the bone marrow and skin biopsies, a diagnosis of IVBCL was made. Unfortunately, no progress was made clinically, and the patient was transitioned to comfort measures. Upon the patient’s death, his family expressed interest in participating in IVBCL research and agreed to a limited autopsy consisting of numerous skin biopsies to evaluate different body sites and biopsy types (normal skin vs hemangiomas) to ascertain whether diagnostic yield could be increased by performing selective biopsies of hemangiomas if IVBCL was suspected.

Twenty-four postmortem 4-mm punch biopsies containing subcutaneous adipose tissue were taken within 24 hours of the death of the patient before embalming. The biopsies were taken from all regions of the body except the head and neck for cosmetic preservation of the decedent. Eighteen of the biopsies were taken from random sites of normal-appearing skin; the remaining 6 were taken from clinically identifiable cherry hemangiomas (5 on the trunk and 1 on the thigh). There was a variable degree of livor mortis in the dependent areas of the body, which was included in the random biopsies from the back to ensure any pooling of dependent blood would not alter the findings.

A histopathologic examination by a board-certified dermatopathologist (M.P.) on a single hematoxylin-eosin–stained level was performed to evaluate each biopsy for superficial involvement and deep involvement by IVBCL. Superficial involvement was defined as dermal involvement at or above the level of the eccrine sweat glands; deep involvement was defined as dermal involvement beneath the eccrine sweat glands and all subcutaneous fat present. Skin and bone marrow biopsies used to make the original diagnosis prior to the patient’s death were reviewed, including CD20 immunohistochemistry for morphologic comparison to the study slides. Involvement was graded as 0 to 3+ (eTable).

Results

Results from all 24 biopsies are shown in the eTable. Twenty-two (91.7%) biopsies showed at least focal involvement by IVBCL. Nine (37.5%) biopsies showed more deep vs superficial involvement of the same site. On average, the 6 biopsies from clinically detected hemangiomas showed more involvement by IVBCL than the random biopsies (eFigures 1 and 2A). The superficial involvement of skin with a hemangioma showed an average score of 2.33 v 0.78 when compared with the superficial aspect of the random biopsies; the deep involvement of skin with a hemangioma showed an average score of 2.67 vs 1.16 when compared with the deep aspect of the random biopsies (eFigure 2B).

Comment

Intravascular large B-cell lymphoma is an aggressive malignancy that traditionally is difficult to diagnose. Many efforts have been made to improve detection and early diagnosis. As cutaneous involvement is common and sometimes the only sign of disease, dermatologists may be called upon to evaluate and biopsy patients with this suspected diagnosis. The purpose of our study was to improve diagnostic efficacy by methodically performing numerous biopsies and assessing the level of involvement of the superficial and deep skin as well as involvement of hemangiomas. The goal of this meticulous approach was to identify the highest-yield areas for biopsy with minimal impact on the patient. Our results showed that random skin biopsies are an effective way to identify IVBCL. Twenty-two (91.7%) biopsies contained at least focal lymphoma cells. Although the 2 biopsies that showed no tumor cells at all happened to both be from the left arm, this is believed to be coincidental. No discernable pattern was identified regarding involvement and anatomic region. Even though 20 (83.3%) biopsies showed superficial involvement, deep biopsy is essential, as 9 (37.5%) biopsies showed increased deep involvement compared to superficial involvement. Therefore, a deep punch biopsy is essential for maximum sensitivity.

Hemangiomas provide a potential target that could increase the sensitivity of a biopsy in the absence of clinical findings, when the disease in question is exclusively intravascular. The data gathered in this study support this idea, as biopsies from hemangiomas showed increased involvement compared to random biopsies, both superficially and deep (2.33 vs 0.78 and 2.67 vs 1.16, respectively). Interestingly, the hemangioma biopsy sites showed increased deep and superficial involvement, despite these typical cherry hemangiomas only involving the superficial dermis. One possible explanation for this is that the hemangiomas have larger-caliber feeder vessels with increased blood flow beneath them. It would then follow that this increased vasculature would increase the chances of identifying intravascular lymphoma cells. This finding further accentuates the need for a deep punch biopsy containing subcutaneous fat. 

Completing the study in the setting of an autopsy provided the advantage of being able to take numerous biopsies without increased harm to the patient. This extensive set of biopsies would not be reasonable to complete on a living patient. This study also has limitations. Although this patient did fall within the typical demographics for patients with IVBCL, the data were still limited to 1 patient. This autopsy format (on a patient whose cause of death was indeed IVBCL) also implies terminal disease, which may mean the patient had a larger disease burden than a living patient who would typically be biopsied. Although this increased disease burden may have increased the sensitivity of finding IVBCL in the biopsies of this study, this further emphasizes the importance of trying to determine any factors that could increase sensitivity in a living patient with a lower disease burden.

Conclusion

Skin biopsies can provide a sensitive, low-cost, and low-morbidity method to assess a patient for IVBCL. Though random skin biopsies can yield valuable information, deep, 4-mm punch biopsies of clinically identifiable hemangiomas may provide the highest sensitivity for IVBCL.

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Epithelioid Fibrous Histiocytoma

In our patient, immunohistochemical stains for Factor XIIIa, CD68, and anaplastic lymphoma kinase (ALK) 1 confirmed the diagnosis of epithelioid fibrous histiocytoma (EFH). The location and relatively large size of the lesion led to a joint decision by the patient and physician to perform a complete excision, which was done with no complications.

Once considered a rare variant of dermatofibroma, EFH most commonly manifests as a solitary, vascular-appearing or flesh-colored papule or nodule on the legs. It often develops in the fifth decade of life with greater prevalence in men.^1-5 Our patient is one of the few known cases of EFH in children that have been reported in the literature.^3,6 Although EFH is benign, complete excision typically is performed due to the rarity of the lesion.³

The overexpression of ALK distinguishes EFH from other fibrohistiocytic lesions (Figure 1).⁵ The most common fusion partners are sequestosome 1 and vinculin (VCL), which account for more than 70% of cases.^3,5,7 Interestingly, VCL-ALK fusions have been reported to occur in a subset of pediatric renal cell carcinomas and recently in an ovoid spindle cell neoplasm considered to be a low-grade sarcoma.^3,7-9 Further studies have identified less common fusion partners, including the dynactin subunit 1, ETS variant transcription factor 6, protein-tyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1, sperm antigen with calponin homology and coiled-coil domains 1, tropomyosin 3, protein kinase cAMP-dependent type II regulatory subunit alpha, melanophilin, and Echinoderm microtubule-associated protein-like 4 genes.^3,8

In contrast to benign fibrous histiocytomas, EFHs primarily consist of epithelioid cells, have well-defined borders, exhibit prominent vascularity, usually are situated close to the epidermis, and lack multinucleated cells or histiocytes laden with lipids or hemosiderin.² The characteristic histopathologic finding is rounded or angulated epithelioid cells, with eosinophilic cytoplasm accounting for more than 50% of the tumor cell population.^1-3,5 The nuclei of the epithelioid cells are rounded and vesicular with small eosinophilic nucleoli and low mitotic activity. Common clinical features include an exophytic nodule with a classic epidermal collarette and an epidermis that exhibits variable degrees of hyperplasia.^1-3,5 Epithelioid fibrous histiocytomas often are confined to the superficial dermis and rarely extend to the subcutaneous layer. The stroma is collagenous with prominent vascularity, although older lesions can become more hyalinized and sclerotic.³ Histopathologically, these tumors can be a diagnostic challenge, as they often are mistaken for other fibrohistiocytic or melanocytic lesions.

Atypical fibroxanthoma (AFX) manifests as a dome-shaped exophytic nodule that can rapidly grow to 1 to 2 cm. Historically, it was thought to be a pseudomalignancy, but most investigators consider it within the spectrum of pleomorphic dermal sarcoma and undifferentiated pleomorphic sarcoma. Atypical fibroxanthoma usually occurs on the head and neck in elderly patients with sun-damaged skin. Histopathologically, the neoplastic cells of AFX range from atypical spindle cells and pleomorphic round to polygonal epithelioid cells to large, irregularly shaped multinucleated cells, some with foamy cytoplasm (Figure 2). The atypical spindle cells stain diffusely positive for CD10 and vimentin, while small subpopulations stain positively for CD68 or CD163 and procollagen 1. Smooth muscle actin inconsistently stains the tumor, and when it does, the staining typically is faint and patchy. Atypical fibroxanthomas usually do not stain positively for melanocytic, skeletal muscle, or keratinocytic markers.

Cellular dermatofibroma typically manifests as small, dome-shaped papules on the arms and legs that normally range from a few millimeters to 1 cm but occasionally measure up to 2 cm. Histopathologically, there are interweaving fascicles of spindle cells with hyperchromatic nuclei and peripheral splaying of the plump spindle cells that wrap around collagen bundles, known as collagen trapping (Figure 3). Unlike EFH, multinucleated cells and histiocytes with abundant lipids and hemosiderin often accompany the spindle cells in cellular dermatofibromas, which stain strongly positive for CD10 and vimentin, similar to AFX and EFH. The smooth muscle actin–staining pattern usually is faint and patchy, and in some cases, cellular dermatofibroma may not stain at all. Factor XIIIa and CD68 highlight the 2 populations of cells—fibroblasts and histiocytes—that make up the lesion.⁴

Epithelioid sarcoma comprises 2 types: distal (or conventional) type occurring on the distal arms and legs, particularly the hands and fingers of young adults, and proximal type occurring on the trunk and proximal extremities, including the upper arms and thighs.¹⁰ Epithelioid sarcoma is a rare aggressive malignancy that usually manifests as a firm nodule, sometimes with ulceration depending on the size. Histopathologically, diffuse dermal proliferation of ovoid to polygonal epithelioid cells arranged in short fascicles and nodular aggregations is observed (Figure 4). Spindle cells may be observed at the periphery of the lesion. Areas of necrosis are a frequent finding and a helpful diagnostic clue. Nearly all cases stain positively for pancytokeratin, CAM5.2, epithelial membrane antigen, and vimentin, and approximately half stain positively for CD34; there are variable expressions of ERG and smooth muscle actin.¹⁰ In most cases, epithelioid sarcoma does not stain positively for S100 or CD68. The majority (90%) of cases harbor a mutation in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene, resulting in the loss of INI1 protein expression, which can be demonstrated by immunohistochemistry. ¹⁰ As the cytologic atypia usually is minimal, epithelioid sarcoma may be misdiagnosed as a necrotizing granuloma and benign fibrous lesions, particularly when superficial or small partial biopsies are performed.

Intradermal Spitz nevi can measure from a few millimeters to more than 2 cm and can range from pink to brown to black. The most common locations are the lower extremities as well as the head and neck. Histopathologically, intradermal Spitz nevi have nests of large epithelioid melanocytes with large nuclei and abundant cytoplasm (eFigure). Nuclear pseudo-inclusions, which are cytoplasmic invaginations into the nucleus, are frequent. Unlike the other conditions in the differential, these entities stain positively for melanocytic markers—S100, SOX10, and Melan-A—but not CD68 or CD163.11 A variety of kinase fusions are observed in Spitz nevi, including the ALK gene, neurotrophic tyrosine receptor kinase, ROS proto-oncogene 1, megakaryocyte-erythroid progenitor, and v-raf murine sarcoma viral oncogene homolog B1 genes.¹²

THE DIAGNOSIS: Epithelioid Fibrous Histiocytoma

In our patient, immunohistochemical stains for Factor XIIIa, CD68, and anaplastic lymphoma kinase (ALK) 1 confirmed the diagnosis of epithelioid fibrous histiocytoma (EFH). The location and relatively large size of the lesion led to a joint decision by the patient and physician to perform a complete excision, which was done with no complications.

Once considered a rare variant of dermatofibroma, EFH most commonly manifests as a solitary, vascular-appearing or flesh-colored papule or nodule on the legs. It often develops in the fifth decade of life with greater prevalence in men.^1-5 Our patient is one of the few known cases of EFH in children that have been reported in the literature.^3,6 Although EFH is benign, complete excision typically is performed due to the rarity of the lesion.³

The overexpression of ALK distinguishes EFH from other fibrohistiocytic lesions (Figure 1).⁵ The most common fusion partners are sequestosome 1 and vinculin (VCL), which account for more than 70% of cases.^3,5,7 Interestingly, VCL-ALK fusions have been reported to occur in a subset of pediatric renal cell carcinomas and recently in an ovoid spindle cell neoplasm considered to be a low-grade sarcoma.^3,7-9 Further studies have identified less common fusion partners, including the dynactin subunit 1, ETS variant transcription factor 6, protein-tyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1, sperm antigen with calponin homology and coiled-coil domains 1, tropomyosin 3, protein kinase cAMP-dependent type II regulatory subunit alpha, melanophilin, and Echinoderm microtubule-associated protein-like 4 genes.^3,8

In contrast to benign fibrous histiocytomas, EFHs primarily consist of epithelioid cells, have well-defined borders, exhibit prominent vascularity, usually are situated close to the epidermis, and lack multinucleated cells or histiocytes laden with lipids or hemosiderin.² The characteristic histopathologic finding is rounded or angulated epithelioid cells, with eosinophilic cytoplasm accounting for more than 50% of the tumor cell population.^1-3,5 The nuclei of the epithelioid cells are rounded and vesicular with small eosinophilic nucleoli and low mitotic activity. Common clinical features include an exophytic nodule with a classic epidermal collarette and an epidermis that exhibits variable degrees of hyperplasia.^1-3,5 Epithelioid fibrous histiocytomas often are confined to the superficial dermis and rarely extend to the subcutaneous layer. The stroma is collagenous with prominent vascularity, although older lesions can become more hyalinized and sclerotic.³ Histopathologically, these tumors can be a diagnostic challenge, as they often are mistaken for other fibrohistiocytic or melanocytic lesions.

Atypical fibroxanthoma (AFX) manifests as a dome-shaped exophytic nodule that can rapidly grow to 1 to 2 cm. Historically, it was thought to be a pseudomalignancy, but most investigators consider it within the spectrum of pleomorphic dermal sarcoma and undifferentiated pleomorphic sarcoma. Atypical fibroxanthoma usually occurs on the head and neck in elderly patients with sun-damaged skin. Histopathologically, the neoplastic cells of AFX range from atypical spindle cells and pleomorphic round to polygonal epithelioid cells to large, irregularly shaped multinucleated cells, some with foamy cytoplasm (Figure 2). The atypical spindle cells stain diffusely positive for CD10 and vimentin, while small subpopulations stain positively for CD68 or CD163 and procollagen 1. Smooth muscle actin inconsistently stains the tumor, and when it does, the staining typically is faint and patchy. Atypical fibroxanthomas usually do not stain positively for melanocytic, skeletal muscle, or keratinocytic markers.

Cellular dermatofibroma typically manifests as small, dome-shaped papules on the arms and legs that normally range from a few millimeters to 1 cm but occasionally measure up to 2 cm. Histopathologically, there are interweaving fascicles of spindle cells with hyperchromatic nuclei and peripheral splaying of the plump spindle cells that wrap around collagen bundles, known as collagen trapping (Figure 3). Unlike EFH, multinucleated cells and histiocytes with abundant lipids and hemosiderin often accompany the spindle cells in cellular dermatofibromas, which stain strongly positive for CD10 and vimentin, similar to AFX and EFH. The smooth muscle actin–staining pattern usually is faint and patchy, and in some cases, cellular dermatofibroma may not stain at all. Factor XIIIa and CD68 highlight the 2 populations of cells—fibroblasts and histiocytes—that make up the lesion.⁴

Epithelioid sarcoma comprises 2 types: distal (or conventional) type occurring on the distal arms and legs, particularly the hands and fingers of young adults, and proximal type occurring on the trunk and proximal extremities, including the upper arms and thighs.¹⁰ Epithelioid sarcoma is a rare aggressive malignancy that usually manifests as a firm nodule, sometimes with ulceration depending on the size. Histopathologically, diffuse dermal proliferation of ovoid to polygonal epithelioid cells arranged in short fascicles and nodular aggregations is observed (Figure 4). Spindle cells may be observed at the periphery of the lesion. Areas of necrosis are a frequent finding and a helpful diagnostic clue. Nearly all cases stain positively for pancytokeratin, CAM5.2, epithelial membrane antigen, and vimentin, and approximately half stain positively for CD34; there are variable expressions of ERG and smooth muscle actin.¹⁰ In most cases, epithelioid sarcoma does not stain positively for S100 or CD68. The majority (90%) of cases harbor a mutation in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene, resulting in the loss of INI1 protein expression, which can be demonstrated by immunohistochemistry. ¹⁰ As the cytologic atypia usually is minimal, epithelioid sarcoma may be misdiagnosed as a necrotizing granuloma and benign fibrous lesions, particularly when superficial or small partial biopsies are performed.

Intradermal Spitz nevi can measure from a few millimeters to more than 2 cm and can range from pink to brown to black. The most common locations are the lower extremities as well as the head and neck. Histopathologically, intradermal Spitz nevi have nests of large epithelioid melanocytes with large nuclei and abundant cytoplasm (eFigure). Nuclear pseudo-inclusions, which are cytoplasmic invaginations into the nucleus, are frequent. Unlike the other conditions in the differential, these entities stain positively for melanocytic markers—S100, SOX10, and Melan-A—but not CD68 or CD163.11 A variety of kinase fusions are observed in Spitz nevi, including the ALK gene, neurotrophic tyrosine receptor kinase, ROS proto-oncogene 1, megakaryocyte-erythroid progenitor, and v-raf murine sarcoma viral oncogene homolog B1 genes.¹²

THE DIAGNOSIS: Epithelioid Fibrous Histiocytoma

In our patient, immunohistochemical stains for Factor XIIIa, CD68, and anaplastic lymphoma kinase (ALK) 1 confirmed the diagnosis of epithelioid fibrous histiocytoma (EFH). The location and relatively large size of the lesion led to a joint decision by the patient and physician to perform a complete excision, which was done with no complications.

Once considered a rare variant of dermatofibroma, EFH most commonly manifests as a solitary, vascular-appearing or flesh-colored papule or nodule on the legs. It often develops in the fifth decade of life with greater prevalence in men.^1-5 Our patient is one of the few known cases of EFH in children that have been reported in the literature.^3,6 Although EFH is benign, complete excision typically is performed due to the rarity of the lesion.³

The overexpression of ALK distinguishes EFH from other fibrohistiocytic lesions (Figure 1).⁵ The most common fusion partners are sequestosome 1 and vinculin (VCL), which account for more than 70% of cases.^3,5,7 Interestingly, VCL-ALK fusions have been reported to occur in a subset of pediatric renal cell carcinomas and recently in an ovoid spindle cell neoplasm considered to be a low-grade sarcoma.^3,7-9 Further studies have identified less common fusion partners, including the dynactin subunit 1, ETS variant transcription factor 6, protein-tyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1, sperm antigen with calponin homology and coiled-coil domains 1, tropomyosin 3, protein kinase cAMP-dependent type II regulatory subunit alpha, melanophilin, and Echinoderm microtubule-associated protein-like 4 genes.^3,8

In contrast to benign fibrous histiocytomas, EFHs primarily consist of epithelioid cells, have well-defined borders, exhibit prominent vascularity, usually are situated close to the epidermis, and lack multinucleated cells or histiocytes laden with lipids or hemosiderin.² The characteristic histopathologic finding is rounded or angulated epithelioid cells, with eosinophilic cytoplasm accounting for more than 50% of the tumor cell population.^1-3,5 The nuclei of the epithelioid cells are rounded and vesicular with small eosinophilic nucleoli and low mitotic activity. Common clinical features include an exophytic nodule with a classic epidermal collarette and an epidermis that exhibits variable degrees of hyperplasia.^1-3,5 Epithelioid fibrous histiocytomas often are confined to the superficial dermis and rarely extend to the subcutaneous layer. The stroma is collagenous with prominent vascularity, although older lesions can become more hyalinized and sclerotic.³ Histopathologically, these tumors can be a diagnostic challenge, as they often are mistaken for other fibrohistiocytic or melanocytic lesions.

Atypical fibroxanthoma (AFX) manifests as a dome-shaped exophytic nodule that can rapidly grow to 1 to 2 cm. Historically, it was thought to be a pseudomalignancy, but most investigators consider it within the spectrum of pleomorphic dermal sarcoma and undifferentiated pleomorphic sarcoma. Atypical fibroxanthoma usually occurs on the head and neck in elderly patients with sun-damaged skin. Histopathologically, the neoplastic cells of AFX range from atypical spindle cells and pleomorphic round to polygonal epithelioid cells to large, irregularly shaped multinucleated cells, some with foamy cytoplasm (Figure 2). The atypical spindle cells stain diffusely positive for CD10 and vimentin, while small subpopulations stain positively for CD68 or CD163 and procollagen 1. Smooth muscle actin inconsistently stains the tumor, and when it does, the staining typically is faint and patchy. Atypical fibroxanthomas usually do not stain positively for melanocytic, skeletal muscle, or keratinocytic markers.

Cellular dermatofibroma typically manifests as small, dome-shaped papules on the arms and legs that normally range from a few millimeters to 1 cm but occasionally measure up to 2 cm. Histopathologically, there are interweaving fascicles of spindle cells with hyperchromatic nuclei and peripheral splaying of the plump spindle cells that wrap around collagen bundles, known as collagen trapping (Figure 3). Unlike EFH, multinucleated cells and histiocytes with abundant lipids and hemosiderin often accompany the spindle cells in cellular dermatofibromas, which stain strongly positive for CD10 and vimentin, similar to AFX and EFH. The smooth muscle actin–staining pattern usually is faint and patchy, and in some cases, cellular dermatofibroma may not stain at all. Factor XIIIa and CD68 highlight the 2 populations of cells—fibroblasts and histiocytes—that make up the lesion.⁴

Epithelioid sarcoma comprises 2 types: distal (or conventional) type occurring on the distal arms and legs, particularly the hands and fingers of young adults, and proximal type occurring on the trunk and proximal extremities, including the upper arms and thighs.¹⁰ Epithelioid sarcoma is a rare aggressive malignancy that usually manifests as a firm nodule, sometimes with ulceration depending on the size. Histopathologically, diffuse dermal proliferation of ovoid to polygonal epithelioid cells arranged in short fascicles and nodular aggregations is observed (Figure 4). Spindle cells may be observed at the periphery of the lesion. Areas of necrosis are a frequent finding and a helpful diagnostic clue. Nearly all cases stain positively for pancytokeratin, CAM5.2, epithelial membrane antigen, and vimentin, and approximately half stain positively for CD34; there are variable expressions of ERG and smooth muscle actin.¹⁰ In most cases, epithelioid sarcoma does not stain positively for S100 or CD68. The majority (90%) of cases harbor a mutation in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene, resulting in the loss of INI1 protein expression, which can be demonstrated by immunohistochemistry. ¹⁰ As the cytologic atypia usually is minimal, epithelioid sarcoma may be misdiagnosed as a necrotizing granuloma and benign fibrous lesions, particularly when superficial or small partial biopsies are performed.

Intradermal Spitz nevi can measure from a few millimeters to more than 2 cm and can range from pink to brown to black. The most common locations are the lower extremities as well as the head and neck. Histopathologically, intradermal Spitz nevi have nests of large epithelioid melanocytes with large nuclei and abundant cytoplasm (eFigure). Nuclear pseudo-inclusions, which are cytoplasmic invaginations into the nucleus, are frequent. Unlike the other conditions in the differential, these entities stain positively for melanocytic markers—S100, SOX10, and Melan-A—but not CD68 or CD163.11 A variety of kinase fusions are observed in Spitz nevi, including the ALK gene, neurotrophic tyrosine receptor kinase, ROS proto-oncogene 1, megakaryocyte-erythroid progenitor, and v-raf murine sarcoma viral oncogene homolog B1 genes.¹²

THE DIAGNOSIS: Dermatofibrosarcoma Protuberans

The histologic findings showed fascicular proliferation of relatively monomorphic spindle cells with extensive entrapment of collagen and adipocytes. Immunohistochemical staining showed that the lesional cells were diffusely positive for CD34 and negative for SOX10, S100, desmin, and factor XIIIa. The decision was made to perform cytogenetic testing with fluorescence in situ hybridization to evaluate for the presence of platelet-derived growth factor receptor beta (PDGFB) polypeptide rearrangement, a key biomarker known to be positive in most patients with dermatofibrosarcoma protuberans (DFSP).¹ This rearrangement results in overproduction of PDGFB, continuous activation of platelet-derived growth factor receptor beta, cellular proliferation, and tumor formation.² In our patient, results were positive for the PDGFB polypeptide rearrangement, which confirmed suspected diagnosis of DFSP with fibrous histiocytoma like morphology. The patient was referred for Mohs micrographic surgery for proper management.

Dermatofibrosarcoma protuberans is a rare soft-tissue tumor that involves the dermis, subcutaneous fat, and sometimes muscle and fascia.² Dermatofibrosarcoma protuberans primarily affects young to middle-aged adults, with a slight predilection for individuals in the third to fifth decades of life.³ Lesions preferentially involve the trunk, particularly the shoulder and chest regions, and manifest as poorly circumscribed, locally aggressive mesenchymal neoplasms with a high local recurrence rate but low metastatic potential.^4,5 Clinically, the lesions appear as flesh-colored, rubbery plaques or nodules. A diagnosis of DFSP requires a high index of clinical suspicion, and histologic, immunohistochemical, and molecular testing usually are required for confirmation.

On histopathologic examination, DFSP classically demonstrates uniform, spindle-shaped cells that traditionally are arranged in an intersecting pattern and primarily are based in the dermis (Figure 1).⁵ Infiltration into the underlying tissue is a common feature, with neoplastic extensions causing a classic honeycomb pattern6 that also can be seen in diffuse neurofibroma and may cause diagnostic challenges; however, the immunohistology staining of neurofibroma differs from DFSP in that it stains positive for CD34, SOX-100, and S100, while DFSP has strong and diffuse CD34 immunoreactivity with negative immunostaining for SOX10, S100, desmin, and factor XIIIa.^2,6

Dermatofibrosarcoma protuberans can cause considerable fat infiltration compared to other soft-tissue neoplasms, making this finding suspicious for—if not characteristic of—DFSP. Collagen trapping also can be observed; however, this is more pathognomonic in cellular fibrous histiocytoma, which is a distinct clinical variant of dermatofibromas. Due to its similarity to other lesions, histopathologic examination along with immunostaining can assist in differentiating and accurately diagnosing DFSP.⁶

Cellular fibrous histiocytoma (CFH), a distinct clinical variant of dermatofibromas, is a benign tumor of mesenchymal origin that occurs more commonly on the trunk, arms, and legs. On histologic examination, CFH is composed of spindle-shaped cells with variable amounts of eosinophilic cytoplasm and small, oval-shaped eosinophilic nuclei and collagen trapping (Figure 2).^7,8 Most CFHs occupy the superficial dermis but can extend into the deep reticular dermis, thus mimicking the honeycomb pattern seen in DFSP. This neoplasm can show a similar architecture to DFSP, which is why further investigation including cytogenetics and immunohistochemical staining can help differentiate the two conditions. Cellular fibrous histiocytoma typically stains negative for CD34 and positive for factor XIIIa.⁹ However, CD34 can be positive in a subset of CFHs, with a considerable subset showing peripheral CD34 positivity and a smaller subset showing central CD34 the positivity.¹⁰ This suggests that CD34 cannot be the only factor differentiating these 2 lesions in making a proper dermatopathologic diagnosis.

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that can occur anywhere on the body and typically manifests as a deep, painless, enlarging mass in adults aged 50 to 60 years.¹¹ On histologic examination, SFT consists of randomly arranged cells with a spindle or ovoid shape within a collagenous stroma intermixed with blood vessels with a characteristic staghorn shape (Figure 3).¹¹ Low-grade SFT shows a patternless arrangement with spindle cells, a low number of mitotic figures, and vessels with a staghorn appearance compared to high-grade SFT, which shows hypercellularity with nuclear pleomorphism and a high number of mitotic figures.¹¹ Solitary fibrous tumors are positive for CD34 and STAT-6 and negative for CD31 and typically demonstrate NGFI-A binding protein 2 (NAB2)—signal transducer and activator of transcription 6 (STAT 6) gene fusion.¹¹

Spindle-cell lipomas are rare, benign, slow-growing, lipomatous tumors that typically manifest in men aged 40 to 70 years.¹² These lesions originate most frequently in the subcutaneous tissue of the upper back, posterior neck, and shoulders. The histologic growth pattern of spindle-cell lipomas can mimic other spindle-cell and myxoid tumors, which is why cytogenetic analysis is crucial for differentiating these lesions. On histologic examination, spindle-cell lipomas exhibit a mixture of mature adipocytes, uniform spindle cells, and collagen bundles (eFigure). Spindle-cell lipoma stains positive for CD34 but negative for S100.¹³ In addition, spindle-cell lipomas tend to show structural rearrangements (mainly deletions) of the long arm of chromosome 13 or even losses of whole chromosome 13, which contains the retinoblastoma (RB1) gene.¹³

Pleomorphic dermal sarcoma is a rare mesenchymal tumor that can appear clinically and histologically similar to atypical fibroxanthoma.¹⁴ This lesion often manifests in elderly patients and is strongly associated with chronic sun exposure.¹⁵ Pleomorphic dermal sarcoma is a locally aggressive tumor with metastatic potential to the skin or lymph nodes. On histologic examination, these tumors exhibit pleomorphic atypical epithelioid or spindle cells as well as multinucleated tumor giant cells with possible tumor necrosis, lymphovascular invasion, or perineural infiltration (Figure 4). Pleomorphic dermal sarcoma, typically a diagnosis of exclusion, requires immunohistochemistry to aid in proper identification.¹⁶ These lesions stain positive for CD10 and negative for cytokeratins, desmin, HMB45, CD34, p63, p40, SOX10, and S100.^15,16

THE DIAGNOSIS: Dermatofibrosarcoma Protuberans

The histologic findings showed fascicular proliferation of relatively monomorphic spindle cells with extensive entrapment of collagen and adipocytes. Immunohistochemical staining showed that the lesional cells were diffusely positive for CD34 and negative for SOX10, S100, desmin, and factor XIIIa. The decision was made to perform cytogenetic testing with fluorescence in situ hybridization to evaluate for the presence of platelet-derived growth factor receptor beta (PDGFB) polypeptide rearrangement, a key biomarker known to be positive in most patients with dermatofibrosarcoma protuberans (DFSP).¹ This rearrangement results in overproduction of PDGFB, continuous activation of platelet-derived growth factor receptor beta, cellular proliferation, and tumor formation.² In our patient, results were positive for the PDGFB polypeptide rearrangement, which confirmed suspected diagnosis of DFSP with fibrous histiocytoma like morphology. The patient was referred for Mohs micrographic surgery for proper management.

Dermatofibrosarcoma protuberans is a rare soft-tissue tumor that involves the dermis, subcutaneous fat, and sometimes muscle and fascia.² Dermatofibrosarcoma protuberans primarily affects young to middle-aged adults, with a slight predilection for individuals in the third to fifth decades of life.³ Lesions preferentially involve the trunk, particularly the shoulder and chest regions, and manifest as poorly circumscribed, locally aggressive mesenchymal neoplasms with a high local recurrence rate but low metastatic potential.^4,5 Clinically, the lesions appear as flesh-colored, rubbery plaques or nodules. A diagnosis of DFSP requires a high index of clinical suspicion, and histologic, immunohistochemical, and molecular testing usually are required for confirmation.

On histopathologic examination, DFSP classically demonstrates uniform, spindle-shaped cells that traditionally are arranged in an intersecting pattern and primarily are based in the dermis (Figure 1).⁵ Infiltration into the underlying tissue is a common feature, with neoplastic extensions causing a classic honeycomb pattern6 that also can be seen in diffuse neurofibroma and may cause diagnostic challenges; however, the immunohistology staining of neurofibroma differs from DFSP in that it stains positive for CD34, SOX-100, and S100, while DFSP has strong and diffuse CD34 immunoreactivity with negative immunostaining for SOX10, S100, desmin, and factor XIIIa.^2,6

Dermatofibrosarcoma protuberans can cause considerable fat infiltration compared to other soft-tissue neoplasms, making this finding suspicious for—if not characteristic of—DFSP. Collagen trapping also can be observed; however, this is more pathognomonic in cellular fibrous histiocytoma, which is a distinct clinical variant of dermatofibromas. Due to its similarity to other lesions, histopathologic examination along with immunostaining can assist in differentiating and accurately diagnosing DFSP.⁶

Cellular fibrous histiocytoma (CFH), a distinct clinical variant of dermatofibromas, is a benign tumor of mesenchymal origin that occurs more commonly on the trunk, arms, and legs. On histologic examination, CFH is composed of spindle-shaped cells with variable amounts of eosinophilic cytoplasm and small, oval-shaped eosinophilic nuclei and collagen trapping (Figure 2).^7,8 Most CFHs occupy the superficial dermis but can extend into the deep reticular dermis, thus mimicking the honeycomb pattern seen in DFSP. This neoplasm can show a similar architecture to DFSP, which is why further investigation including cytogenetics and immunohistochemical staining can help differentiate the two conditions. Cellular fibrous histiocytoma typically stains negative for CD34 and positive for factor XIIIa.⁹ However, CD34 can be positive in a subset of CFHs, with a considerable subset showing peripheral CD34 positivity and a smaller subset showing central CD34 the positivity.¹⁰ This suggests that CD34 cannot be the only factor differentiating these 2 lesions in making a proper dermatopathologic diagnosis.

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that can occur anywhere on the body and typically manifests as a deep, painless, enlarging mass in adults aged 50 to 60 years.¹¹ On histologic examination, SFT consists of randomly arranged cells with a spindle or ovoid shape within a collagenous stroma intermixed with blood vessels with a characteristic staghorn shape (Figure 3).¹¹ Low-grade SFT shows a patternless arrangement with spindle cells, a low number of mitotic figures, and vessels with a staghorn appearance compared to high-grade SFT, which shows hypercellularity with nuclear pleomorphism and a high number of mitotic figures.¹¹ Solitary fibrous tumors are positive for CD34 and STAT-6 and negative for CD31 and typically demonstrate NGFI-A binding protein 2 (NAB2)—signal transducer and activator of transcription 6 (STAT 6) gene fusion.¹¹

Spindle-cell lipomas are rare, benign, slow-growing, lipomatous tumors that typically manifest in men aged 40 to 70 years.¹² These lesions originate most frequently in the subcutaneous tissue of the upper back, posterior neck, and shoulders. The histologic growth pattern of spindle-cell lipomas can mimic other spindle-cell and myxoid tumors, which is why cytogenetic analysis is crucial for differentiating these lesions. On histologic examination, spindle-cell lipomas exhibit a mixture of mature adipocytes, uniform spindle cells, and collagen bundles (eFigure). Spindle-cell lipoma stains positive for CD34 but negative for S100.¹³ In addition, spindle-cell lipomas tend to show structural rearrangements (mainly deletions) of the long arm of chromosome 13 or even losses of whole chromosome 13, which contains the retinoblastoma (RB1) gene.¹³

Pleomorphic dermal sarcoma is a rare mesenchymal tumor that can appear clinically and histologically similar to atypical fibroxanthoma.¹⁴ This lesion often manifests in elderly patients and is strongly associated with chronic sun exposure.¹⁵ Pleomorphic dermal sarcoma is a locally aggressive tumor with metastatic potential to the skin or lymph nodes. On histologic examination, these tumors exhibit pleomorphic atypical epithelioid or spindle cells as well as multinucleated tumor giant cells with possible tumor necrosis, lymphovascular invasion, or perineural infiltration (Figure 4). Pleomorphic dermal sarcoma, typically a diagnosis of exclusion, requires immunohistochemistry to aid in proper identification.¹⁶ These lesions stain positive for CD10 and negative for cytokeratins, desmin, HMB45, CD34, p63, p40, SOX10, and S100.^15,16

THE DIAGNOSIS: Dermatofibrosarcoma Protuberans

The histologic findings showed fascicular proliferation of relatively monomorphic spindle cells with extensive entrapment of collagen and adipocytes. Immunohistochemical staining showed that the lesional cells were diffusely positive for CD34 and negative for SOX10, S100, desmin, and factor XIIIa. The decision was made to perform cytogenetic testing with fluorescence in situ hybridization to evaluate for the presence of platelet-derived growth factor receptor beta (PDGFB) polypeptide rearrangement, a key biomarker known to be positive in most patients with dermatofibrosarcoma protuberans (DFSP).¹ This rearrangement results in overproduction of PDGFB, continuous activation of platelet-derived growth factor receptor beta, cellular proliferation, and tumor formation.² In our patient, results were positive for the PDGFB polypeptide rearrangement, which confirmed suspected diagnosis of DFSP with fibrous histiocytoma like morphology. The patient was referred for Mohs micrographic surgery for proper management.

Dermatofibrosarcoma protuberans is a rare soft-tissue tumor that involves the dermis, subcutaneous fat, and sometimes muscle and fascia.² Dermatofibrosarcoma protuberans primarily affects young to middle-aged adults, with a slight predilection for individuals in the third to fifth decades of life.³ Lesions preferentially involve the trunk, particularly the shoulder and chest regions, and manifest as poorly circumscribed, locally aggressive mesenchymal neoplasms with a high local recurrence rate but low metastatic potential.^4,5 Clinically, the lesions appear as flesh-colored, rubbery plaques or nodules. A diagnosis of DFSP requires a high index of clinical suspicion, and histologic, immunohistochemical, and molecular testing usually are required for confirmation.

On histopathologic examination, DFSP classically demonstrates uniform, spindle-shaped cells that traditionally are arranged in an intersecting pattern and primarily are based in the dermis (Figure 1).⁵ Infiltration into the underlying tissue is a common feature, with neoplastic extensions causing a classic honeycomb pattern6 that also can be seen in diffuse neurofibroma and may cause diagnostic challenges; however, the immunohistology staining of neurofibroma differs from DFSP in that it stains positive for CD34, SOX-100, and S100, while DFSP has strong and diffuse CD34 immunoreactivity with negative immunostaining for SOX10, S100, desmin, and factor XIIIa.^2,6

Dermatofibrosarcoma protuberans can cause considerable fat infiltration compared to other soft-tissue neoplasms, making this finding suspicious for—if not characteristic of—DFSP. Collagen trapping also can be observed; however, this is more pathognomonic in cellular fibrous histiocytoma, which is a distinct clinical variant of dermatofibromas. Due to its similarity to other lesions, histopathologic examination along with immunostaining can assist in differentiating and accurately diagnosing DFSP.⁶

Cellular fibrous histiocytoma (CFH), a distinct clinical variant of dermatofibromas, is a benign tumor of mesenchymal origin that occurs more commonly on the trunk, arms, and legs. On histologic examination, CFH is composed of spindle-shaped cells with variable amounts of eosinophilic cytoplasm and small, oval-shaped eosinophilic nuclei and collagen trapping (Figure 2).^7,8 Most CFHs occupy the superficial dermis but can extend into the deep reticular dermis, thus mimicking the honeycomb pattern seen in DFSP. This neoplasm can show a similar architecture to DFSP, which is why further investigation including cytogenetics and immunohistochemical staining can help differentiate the two conditions. Cellular fibrous histiocytoma typically stains negative for CD34 and positive for factor XIIIa.⁹ However, CD34 can be positive in a subset of CFHs, with a considerable subset showing peripheral CD34 positivity and a smaller subset showing central CD34 the positivity.¹⁰ This suggests that CD34 cannot be the only factor differentiating these 2 lesions in making a proper dermatopathologic diagnosis.

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that can occur anywhere on the body and typically manifests as a deep, painless, enlarging mass in adults aged 50 to 60 years.¹¹ On histologic examination, SFT consists of randomly arranged cells with a spindle or ovoid shape within a collagenous stroma intermixed with blood vessels with a characteristic staghorn shape (Figure 3).¹¹ Low-grade SFT shows a patternless arrangement with spindle cells, a low number of mitotic figures, and vessels with a staghorn appearance compared to high-grade SFT, which shows hypercellularity with nuclear pleomorphism and a high number of mitotic figures.¹¹ Solitary fibrous tumors are positive for CD34 and STAT-6 and negative for CD31 and typically demonstrate NGFI-A binding protein 2 (NAB2)—signal transducer and activator of transcription 6 (STAT 6) gene fusion.¹¹

Spindle-cell lipomas are rare, benign, slow-growing, lipomatous tumors that typically manifest in men aged 40 to 70 years.¹² These lesions originate most frequently in the subcutaneous tissue of the upper back, posterior neck, and shoulders. The histologic growth pattern of spindle-cell lipomas can mimic other spindle-cell and myxoid tumors, which is why cytogenetic analysis is crucial for differentiating these lesions. On histologic examination, spindle-cell lipomas exhibit a mixture of mature adipocytes, uniform spindle cells, and collagen bundles (eFigure). Spindle-cell lipoma stains positive for CD34 but negative for S100.¹³ In addition, spindle-cell lipomas tend to show structural rearrangements (mainly deletions) of the long arm of chromosome 13 or even losses of whole chromosome 13, which contains the retinoblastoma (RB1) gene.¹³

Pleomorphic dermal sarcoma is a rare mesenchymal tumor that can appear clinically and histologically similar to atypical fibroxanthoma.¹⁴ This lesion often manifests in elderly patients and is strongly associated with chronic sun exposure.¹⁵ Pleomorphic dermal sarcoma is a locally aggressive tumor with metastatic potential to the skin or lymph nodes. On histologic examination, these tumors exhibit pleomorphic atypical epithelioid or spindle cells as well as multinucleated tumor giant cells with possible tumor necrosis, lymphovascular invasion, or perineural infiltration (Figure 4). Pleomorphic dermal sarcoma, typically a diagnosis of exclusion, requires immunohistochemistry to aid in proper identification.¹⁶ These lesions stain positive for CD10 and negative for cytokeratins, desmin, HMB45, CD34, p63, p40, SOX10, and S100.^15,16

THE DIAGNOSIS: Plaquelike Myofibroblastic Tumor

An incisional biopsy of the plaque demonstrated a hypercellular proliferation of bland spindle cells in the dermis that infiltrated the subcutis. The overlying epidermis was mildly acanthotic with both ulceration and follicular induction. There was trapping of individual adipocytes in a honeycomb pattern with foci of erythrocyte extravasation, microvesiculation, and widened fibrous septa (Figure 1). Immunohistochemistry was positive for vimentin, actin, and smooth muscle actin (SMA)(Figure 2A). Variable positivity for Factor XIIIa antibodies was noted. CD68 staining was focal positive, suggesting fibrohistiocytic lineage. Expression of CD31, CD34, S100, and anaplastic lymphoma kinase was negative, and Ki-67 was present in less than 10% of cells (Figure 2B).

We reviewed the case in conjunction with a soft-tissue pathologist (Y.L.), and based on the clinical and immunophenotypic features, a diagnosis of plaquelike myofibroblastic tumor (PLMT) was made. The patient’s parents refused further treatment, and there was no sign of disease progression at 6-month follow-up.

Plaquelike myofibroblastic tumor is an unusual pediatric dermal tumor that was first described by Clarke et al¹ in 2007. Clinical manifestation of PLMT on the right abdomen was unique in our patient, as the lesions typically present as indurated plaques on the lower back, but the central ulceration in our case resembled a report by Marqueling et al.² Ulceration and induration of PLMT developing at 8 months of age can suggest an aggressive disease course corresponding with deep infiltration and is seen mostly in children.

The histopathologic features of PLMT include an acanthotic epidermis and follicular induction, which also are characteristic of dermatofibroma (DF). The proliferation of spindle cells extended deep into the fat with foci of erythrocyte extravasation and microvesiculation of the stroma similar to nodular fasciitis and proliferative fasciitis. The presentation of infiltrating and expanding fibrous septae and trapping of individual adipocytes in a honeycomb pattern is similar to dermatofibrosarcoma protuberans (DFSP). Most cases of PLMT are positive for SMA. Factor XIIIa typically is variably positive, and in one report, 31% (4/13) of cases showed positive staining for calponin.³ Rapid growth, ulceration, and recurrence emphasize that PLMT can be locally aggressive, similar to DFSP.⁴

The main differential diagnoses include DF and its variants, dermatomyofibroma, DFSP, and proliferative fasciitis.^3,5 In the cases mentioned above, microscopic features were similar with a relatively well-circumscribed proliferation of spindle cells arranged in short fascicles through the entire reticular dermis, and the overlying epidermis was acanthotic.

Dermatofibroma commonly manifests in adults as a minor nodular lesion (commonly <1 cm), and usually is located on the legs. It has several clinical and histologic variants, including multiple clustered DF (MCDF)—a rare condition that has been reported in children and young adults and generally appears in the first and second decades of life. Of the reported cases of MCDF, immunohistochemical staining for SMA was performed in 8 cases. All these cases showed negative or minimal staining.^3-5 Smooth muscle actin staining in DFs is negative, or weak and patchy, unlike in PLMT where it is diffuse, uniform, and strong.

Dermatofibrosarcoma protuberans typically occurs in young adults and manifests as dermal and subcutaneous nodular/multinodular or plaquelike masses, with rare congenital cases. Immunohistochemical staining for CD34, which typically is firmly and diffusely positive, is the most reliable marker of DFSP.⁶ Factor XIIIA in DFSP typically is negative for focal staining, mainly at periphery or in scattered dendritic cells. The prognosis of DFSP generally is excellent, with local recurrences in up to 30% of cases and extremely low metastatic potential (essentially only in cases with fibrosarcomatous transformation).⁶ Dermatomyofibroma is another rare benign dermal myofibroblastic tumor that typically manifests with indurated hyperpigmented or erythematous plaques or nodules on the shoulders and torso.⁶ This condition occurs mainly in adolescents and young adults, unlike PLMT. The most striking features of dermatomyofibroma are the horizontal orientation of the spindle cell nuclei and the pattern of the proliferation concerning the adnexal structures, especially hair follicles. The hair follicles have a normal appearance, and the proliferation extends up to each follicle, then continues to the other side without any displacement of the follicle. Tumor cells are variably positive for SMA in dermatomyofibromas and are negative for muscle-specific actin, desmin, S100, CD34, and Factor XIIIA.⁶

Immunohistochemistry can be very useful in differentiating PLMT from other conditions. Neoplastic cells stain positively for CD34 but not for Factor XIIIa and SMA in cases of DFSP. Dermatofibroma and its variants always present with collagen trapping at the periphery of the lesions and may demonstrate foamy macrophages, hemosiderin, or plasma cells FXIIIA(+), CD34(-), and variable SMA reactivity. This positivity usually is less prominent in DF than in PLMT. Neoplastic cells in dermatomyofibroma often stain positive for calponin, but only focally for SMA. The clinical features of dermatomyofibroma include early onset, large size, multiple nodules, and plaquelike morphology. Moulonguet et al⁴ hypothesized that, although MCDF and PLMT appear to show some distinctive clinical and histologic features, they also show similarities that could suggest they form part of the myofibroblastic spectrum. Furthermore, Moradi et al⁷ also considered them as part of the same disease spectrum because of their overlapping clinical, histologic, and immunohistochemical features.

The microscopic features in our case are notable, as the lesion demonstrated overlying acanthosis and follicular induction, resembling DF. The stroma contained microvesicular changes and erythrocyte extravasation, characteristic of nodular or proliferative fasciitis. Additionally, densely packed spindle cells infiltrated deep into the subcutaneous adipose tissue, similar to DFSP.^2,3 Our findings expand on the reported histopathologic spectrum of this tumor to date.

THE DIAGNOSIS: Plaquelike Myofibroblastic Tumor

An incisional biopsy of the plaque demonstrated a hypercellular proliferation of bland spindle cells in the dermis that infiltrated the subcutis. The overlying epidermis was mildly acanthotic with both ulceration and follicular induction. There was trapping of individual adipocytes in a honeycomb pattern with foci of erythrocyte extravasation, microvesiculation, and widened fibrous septa (Figure 1). Immunohistochemistry was positive for vimentin, actin, and smooth muscle actin (SMA)(Figure 2A). Variable positivity for Factor XIIIa antibodies was noted. CD68 staining was focal positive, suggesting fibrohistiocytic lineage. Expression of CD31, CD34, S100, and anaplastic lymphoma kinase was negative, and Ki-67 was present in less than 10% of cells (Figure 2B).

We reviewed the case in conjunction with a soft-tissue pathologist (Y.L.), and based on the clinical and immunophenotypic features, a diagnosis of plaquelike myofibroblastic tumor (PLMT) was made. The patient’s parents refused further treatment, and there was no sign of disease progression at 6-month follow-up.

Plaquelike myofibroblastic tumor is an unusual pediatric dermal tumor that was first described by Clarke et al¹ in 2007. Clinical manifestation of PLMT on the right abdomen was unique in our patient, as the lesions typically present as indurated plaques on the lower back, but the central ulceration in our case resembled a report by Marqueling et al.² Ulceration and induration of PLMT developing at 8 months of age can suggest an aggressive disease course corresponding with deep infiltration and is seen mostly in children.

The histopathologic features of PLMT include an acanthotic epidermis and follicular induction, which also are characteristic of dermatofibroma (DF). The proliferation of spindle cells extended deep into the fat with foci of erythrocyte extravasation and microvesiculation of the stroma similar to nodular fasciitis and proliferative fasciitis. The presentation of infiltrating and expanding fibrous septae and trapping of individual adipocytes in a honeycomb pattern is similar to dermatofibrosarcoma protuberans (DFSP). Most cases of PLMT are positive for SMA. Factor XIIIa typically is variably positive, and in one report, 31% (4/13) of cases showed positive staining for calponin.³ Rapid growth, ulceration, and recurrence emphasize that PLMT can be locally aggressive, similar to DFSP.⁴

The main differential diagnoses include DF and its variants, dermatomyofibroma, DFSP, and proliferative fasciitis.^3,5 In the cases mentioned above, microscopic features were similar with a relatively well-circumscribed proliferation of spindle cells arranged in short fascicles through the entire reticular dermis, and the overlying epidermis was acanthotic.

Dermatofibroma commonly manifests in adults as a minor nodular lesion (commonly <1 cm), and usually is located on the legs. It has several clinical and histologic variants, including multiple clustered DF (MCDF)—a rare condition that has been reported in children and young adults and generally appears in the first and second decades of life. Of the reported cases of MCDF, immunohistochemical staining for SMA was performed in 8 cases. All these cases showed negative or minimal staining.^3-5 Smooth muscle actin staining in DFs is negative, or weak and patchy, unlike in PLMT where it is diffuse, uniform, and strong.

Dermatofibrosarcoma protuberans typically occurs in young adults and manifests as dermal and subcutaneous nodular/multinodular or plaquelike masses, with rare congenital cases. Immunohistochemical staining for CD34, which typically is firmly and diffusely positive, is the most reliable marker of DFSP.⁶ Factor XIIIA in DFSP typically is negative for focal staining, mainly at periphery or in scattered dendritic cells. The prognosis of DFSP generally is excellent, with local recurrences in up to 30% of cases and extremely low metastatic potential (essentially only in cases with fibrosarcomatous transformation).⁶ Dermatomyofibroma is another rare benign dermal myofibroblastic tumor that typically manifests with indurated hyperpigmented or erythematous plaques or nodules on the shoulders and torso.⁶ This condition occurs mainly in adolescents and young adults, unlike PLMT. The most striking features of dermatomyofibroma are the horizontal orientation of the spindle cell nuclei and the pattern of the proliferation concerning the adnexal structures, especially hair follicles. The hair follicles have a normal appearance, and the proliferation extends up to each follicle, then continues to the other side without any displacement of the follicle. Tumor cells are variably positive for SMA in dermatomyofibromas and are negative for muscle-specific actin, desmin, S100, CD34, and Factor XIIIA.⁶

Immunohistochemistry can be very useful in differentiating PLMT from other conditions. Neoplastic cells stain positively for CD34 but not for Factor XIIIa and SMA in cases of DFSP. Dermatofibroma and its variants always present with collagen trapping at the periphery of the lesions and may demonstrate foamy macrophages, hemosiderin, or plasma cells FXIIIA(+), CD34(-), and variable SMA reactivity. This positivity usually is less prominent in DF than in PLMT. Neoplastic cells in dermatomyofibroma often stain positive for calponin, but only focally for SMA. The clinical features of dermatomyofibroma include early onset, large size, multiple nodules, and plaquelike morphology. Moulonguet et al⁴ hypothesized that, although MCDF and PLMT appear to show some distinctive clinical and histologic features, they also show similarities that could suggest they form part of the myofibroblastic spectrum. Furthermore, Moradi et al⁷ also considered them as part of the same disease spectrum because of their overlapping clinical, histologic, and immunohistochemical features.

The microscopic features in our case are notable, as the lesion demonstrated overlying acanthosis and follicular induction, resembling DF. The stroma contained microvesicular changes and erythrocyte extravasation, characteristic of nodular or proliferative fasciitis. Additionally, densely packed spindle cells infiltrated deep into the subcutaneous adipose tissue, similar to DFSP.^2,3 Our findings expand on the reported histopathologic spectrum of this tumor to date.

THE DIAGNOSIS: Plaquelike Myofibroblastic Tumor

An incisional biopsy of the plaque demonstrated a hypercellular proliferation of bland spindle cells in the dermis that infiltrated the subcutis. The overlying epidermis was mildly acanthotic with both ulceration and follicular induction. There was trapping of individual adipocytes in a honeycomb pattern with foci of erythrocyte extravasation, microvesiculation, and widened fibrous septa (Figure 1). Immunohistochemistry was positive for vimentin, actin, and smooth muscle actin (SMA)(Figure 2A). Variable positivity for Factor XIIIa antibodies was noted. CD68 staining was focal positive, suggesting fibrohistiocytic lineage. Expression of CD31, CD34, S100, and anaplastic lymphoma kinase was negative, and Ki-67 was present in less than 10% of cells (Figure 2B).

We reviewed the case in conjunction with a soft-tissue pathologist (Y.L.), and based on the clinical and immunophenotypic features, a diagnosis of plaquelike myofibroblastic tumor (PLMT) was made. The patient’s parents refused further treatment, and there was no sign of disease progression at 6-month follow-up.

Plaquelike myofibroblastic tumor is an unusual pediatric dermal tumor that was first described by Clarke et al¹ in 2007. Clinical manifestation of PLMT on the right abdomen was unique in our patient, as the lesions typically present as indurated plaques on the lower back, but the central ulceration in our case resembled a report by Marqueling et al.² Ulceration and induration of PLMT developing at 8 months of age can suggest an aggressive disease course corresponding with deep infiltration and is seen mostly in children.

The histopathologic features of PLMT include an acanthotic epidermis and follicular induction, which also are characteristic of dermatofibroma (DF). The proliferation of spindle cells extended deep into the fat with foci of erythrocyte extravasation and microvesiculation of the stroma similar to nodular fasciitis and proliferative fasciitis. The presentation of infiltrating and expanding fibrous septae and trapping of individual adipocytes in a honeycomb pattern is similar to dermatofibrosarcoma protuberans (DFSP). Most cases of PLMT are positive for SMA. Factor XIIIa typically is variably positive, and in one report, 31% (4/13) of cases showed positive staining for calponin.³ Rapid growth, ulceration, and recurrence emphasize that PLMT can be locally aggressive, similar to DFSP.⁴

The main differential diagnoses include DF and its variants, dermatomyofibroma, DFSP, and proliferative fasciitis.^3,5 In the cases mentioned above, microscopic features were similar with a relatively well-circumscribed proliferation of spindle cells arranged in short fascicles through the entire reticular dermis, and the overlying epidermis was acanthotic.

Dermatofibroma commonly manifests in adults as a minor nodular lesion (commonly <1 cm), and usually is located on the legs. It has several clinical and histologic variants, including multiple clustered DF (MCDF)—a rare condition that has been reported in children and young adults and generally appears in the first and second decades of life. Of the reported cases of MCDF, immunohistochemical staining for SMA was performed in 8 cases. All these cases showed negative or minimal staining.^3-5 Smooth muscle actin staining in DFs is negative, or weak and patchy, unlike in PLMT where it is diffuse, uniform, and strong.

Dermatofibrosarcoma protuberans typically occurs in young adults and manifests as dermal and subcutaneous nodular/multinodular or plaquelike masses, with rare congenital cases. Immunohistochemical staining for CD34, which typically is firmly and diffusely positive, is the most reliable marker of DFSP.⁶ Factor XIIIA in DFSP typically is negative for focal staining, mainly at periphery or in scattered dendritic cells. The prognosis of DFSP generally is excellent, with local recurrences in up to 30% of cases and extremely low metastatic potential (essentially only in cases with fibrosarcomatous transformation).⁶ Dermatomyofibroma is another rare benign dermal myofibroblastic tumor that typically manifests with indurated hyperpigmented or erythematous plaques or nodules on the shoulders and torso.⁶ This condition occurs mainly in adolescents and young adults, unlike PLMT. The most striking features of dermatomyofibroma are the horizontal orientation of the spindle cell nuclei and the pattern of the proliferation concerning the adnexal structures, especially hair follicles. The hair follicles have a normal appearance, and the proliferation extends up to each follicle, then continues to the other side without any displacement of the follicle. Tumor cells are variably positive for SMA in dermatomyofibromas and are negative for muscle-specific actin, desmin, S100, CD34, and Factor XIIIA.⁶

Immunohistochemistry can be very useful in differentiating PLMT from other conditions. Neoplastic cells stain positively for CD34 but not for Factor XIIIa and SMA in cases of DFSP. Dermatofibroma and its variants always present with collagen trapping at the periphery of the lesions and may demonstrate foamy macrophages, hemosiderin, or plasma cells FXIIIA(+), CD34(-), and variable SMA reactivity. This positivity usually is less prominent in DF than in PLMT. Neoplastic cells in dermatomyofibroma often stain positive for calponin, but only focally for SMA. The clinical features of dermatomyofibroma include early onset, large size, multiple nodules, and plaquelike morphology. Moulonguet et al⁴ hypothesized that, although MCDF and PLMT appear to show some distinctive clinical and histologic features, they also show similarities that could suggest they form part of the myofibroblastic spectrum. Furthermore, Moradi et al⁷ also considered them as part of the same disease spectrum because of their overlapping clinical, histologic, and immunohistochemical features.

The microscopic features in our case are notable, as the lesion demonstrated overlying acanthosis and follicular induction, resembling DF. The stroma contained microvesicular changes and erythrocyte extravasation, characteristic of nodular or proliferative fasciitis. Additionally, densely packed spindle cells infiltrated deep into the subcutaneous adipose tissue, similar to DFSP.^2,3 Our findings expand on the reported histopathologic spectrum of this tumor to date.

To the Editor:

A 22-year-old man was referred to our dermatology outpatient department for wartlike growths that gradually developed around a postoperative enteroatmospheric fistula and stoma over the past 4 months. The patient presented for an emergency exploratory laparotomy with a history of perforation peritonitis 1.5 years prior to the current presentation. He also had a small bowel obstruction 5 months prior to the current presentation that resulted in the resection of a large segment of the small bowel. He underwent a diverting loop ileostomy when the abdominal closure was not achieved because of bowel edema, following which he developed a postoperative enteroatmospheric fistula. In addition, the stoma retracted and was followed by dermal dehiscence, which led to notable leakage and resulted in heavy fecal contamination of the midline wound.

At the current presentation, physical examination revealed multiple grayish-white, dome-shaped, moist papules coalescing to form a peristomal pseudoverrucous mass on the lower side of the stoma (Figure 1). The patient experienced mild itching. The lesion showed no signs of erosion, bleeding, or purulent discharge, and there were no nearby lumps or enlarged lymph nodes. The differential diagnosis included peristomal pyoderma gangrenosum, human papillomavirus (HPV) infection, pseudoverrucous papules and nodules (PPNs), squamous cell carcinoma, and exuberant granulation tissue. A skin biopsy was performed, and histopathology revealed hyperkeratosis, moderate papillomatosis, and marked acanthotic hyperplasia seen as downgrowths into the dermis (Figure 2). No koilocytes, atypia, or mitotic figures were present. Abundant neutrophils and few eosinophils were seen in the dermal infiltrate. A final diagnosis of PPN was made based on clinicopathologic correlation. The patient was advised to use a smaller stoma bag and to change the collection pouch frequently to reduce skin contact with fecal matter.

Peristomal skin conditions are reported in 18% to 55% of patients with stomas and include allergic contact dermatitis, mechanical dermatitis, infections, pyoderma gangrenosum, and irritant contact dermatitis.^1,2 Pseudoverrucous papules (also called chronic papillomatous dermatitis or pseudoverrucous lesions) is a rare dermatologic complication found on the skin around stomas,³ most commonly around urostomy stomas. The presence of PPNs around colostomy stomas and the perianal region is extremely rare.^2,4 This condition is the result of chronic irritant dermatitis from frequent exposure to urine or feces, leading to maceration and epidermal hyperplasia. It occurs because of improper sizing of the stoma bag or incorrect positioning or construction of the stoma.⁵

the overuse of topical benzocaine-resorcinol, leading to chronic irritation.⁶ It is clinically characterized by multiple grayish-white, wartlike, confluent papulonodules around areas chronically exposed to moisture. Differential diagnoses such as secondary neoplasms, HPV infection, exuberant granulation tissue, and candidal infections should be considered.³ Final diagnosis is based on clinicopathologic findings, similar to our case. Epidermal growth factor and transforming growth factor are thought to play a role in the pathophysiology of pseudoepitheliomatous hyperplasia. Increased expression of these mediators leads to proliferation of the epidermis into the dermis.⁷ The role of HPV in PPN remains unclear, as not all PPN lesions are positive for HPV and the cutaneous lesions resolve once the source of irritation is removed. Recommended treatment includes local skin care; stoma refitting; and, in severe cases, excision and revision of the stoma.² Dermatologists must be aware of this often-underdiagnosed condition.

To the Editor:

A 22-year-old man was referred to our dermatology outpatient department for wartlike growths that gradually developed around a postoperative enteroatmospheric fistula and stoma over the past 4 months. The patient presented for an emergency exploratory laparotomy with a history of perforation peritonitis 1.5 years prior to the current presentation. He also had a small bowel obstruction 5 months prior to the current presentation that resulted in the resection of a large segment of the small bowel. He underwent a diverting loop ileostomy when the abdominal closure was not achieved because of bowel edema, following which he developed a postoperative enteroatmospheric fistula. In addition, the stoma retracted and was followed by dermal dehiscence, which led to notable leakage and resulted in heavy fecal contamination of the midline wound.

At the current presentation, physical examination revealed multiple grayish-white, dome-shaped, moist papules coalescing to form a peristomal pseudoverrucous mass on the lower side of the stoma (Figure 1). The patient experienced mild itching. The lesion showed no signs of erosion, bleeding, or purulent discharge, and there were no nearby lumps or enlarged lymph nodes. The differential diagnosis included peristomal pyoderma gangrenosum, human papillomavirus (HPV) infection, pseudoverrucous papules and nodules (PPNs), squamous cell carcinoma, and exuberant granulation tissue. A skin biopsy was performed, and histopathology revealed hyperkeratosis, moderate papillomatosis, and marked acanthotic hyperplasia seen as downgrowths into the dermis (Figure 2). No koilocytes, atypia, or mitotic figures were present. Abundant neutrophils and few eosinophils were seen in the dermal infiltrate. A final diagnosis of PPN was made based on clinicopathologic correlation. The patient was advised to use a smaller stoma bag and to change the collection pouch frequently to reduce skin contact with fecal matter.

Peristomal skin conditions are reported in 18% to 55% of patients with stomas and include allergic contact dermatitis, mechanical dermatitis, infections, pyoderma gangrenosum, and irritant contact dermatitis.^1,2 Pseudoverrucous papules (also called chronic papillomatous dermatitis or pseudoverrucous lesions) is a rare dermatologic complication found on the skin around stomas,³ most commonly around urostomy stomas. The presence of PPNs around colostomy stomas and the perianal region is extremely rare.^2,4 This condition is the result of chronic irritant dermatitis from frequent exposure to urine or feces, leading to maceration and epidermal hyperplasia. It occurs because of improper sizing of the stoma bag or incorrect positioning or construction of the stoma.⁵

the overuse of topical benzocaine-resorcinol, leading to chronic irritation.⁶ It is clinically characterized by multiple grayish-white, wartlike, confluent papulonodules around areas chronically exposed to moisture. Differential diagnoses such as secondary neoplasms, HPV infection, exuberant granulation tissue, and candidal infections should be considered.³ Final diagnosis is based on clinicopathologic findings, similar to our case. Epidermal growth factor and transforming growth factor are thought to play a role in the pathophysiology of pseudoepitheliomatous hyperplasia. Increased expression of these mediators leads to proliferation of the epidermis into the dermis.⁷ The role of HPV in PPN remains unclear, as not all PPN lesions are positive for HPV and the cutaneous lesions resolve once the source of irritation is removed. Recommended treatment includes local skin care; stoma refitting; and, in severe cases, excision and revision of the stoma.² Dermatologists must be aware of this often-underdiagnosed condition.

To the Editor:

A 22-year-old man was referred to our dermatology outpatient department for wartlike growths that gradually developed around a postoperative enteroatmospheric fistula and stoma over the past 4 months. The patient presented for an emergency exploratory laparotomy with a history of perforation peritonitis 1.5 years prior to the current presentation. He also had a small bowel obstruction 5 months prior to the current presentation that resulted in the resection of a large segment of the small bowel. He underwent a diverting loop ileostomy when the abdominal closure was not achieved because of bowel edema, following which he developed a postoperative enteroatmospheric fistula. In addition, the stoma retracted and was followed by dermal dehiscence, which led to notable leakage and resulted in heavy fecal contamination of the midline wound.

At the current presentation, physical examination revealed multiple grayish-white, dome-shaped, moist papules coalescing to form a peristomal pseudoverrucous mass on the lower side of the stoma (Figure 1). The patient experienced mild itching. The lesion showed no signs of erosion, bleeding, or purulent discharge, and there were no nearby lumps or enlarged lymph nodes. The differential diagnosis included peristomal pyoderma gangrenosum, human papillomavirus (HPV) infection, pseudoverrucous papules and nodules (PPNs), squamous cell carcinoma, and exuberant granulation tissue. A skin biopsy was performed, and histopathology revealed hyperkeratosis, moderate papillomatosis, and marked acanthotic hyperplasia seen as downgrowths into the dermis (Figure 2). No koilocytes, atypia, or mitotic figures were present. Abundant neutrophils and few eosinophils were seen in the dermal infiltrate. A final diagnosis of PPN was made based on clinicopathologic correlation. The patient was advised to use a smaller stoma bag and to change the collection pouch frequently to reduce skin contact with fecal matter.

Peristomal skin conditions are reported in 18% to 55% of patients with stomas and include allergic contact dermatitis, mechanical dermatitis, infections, pyoderma gangrenosum, and irritant contact dermatitis.^1,2 Pseudoverrucous papules (also called chronic papillomatous dermatitis or pseudoverrucous lesions) is a rare dermatologic complication found on the skin around stomas,³ most commonly around urostomy stomas. The presence of PPNs around colostomy stomas and the perianal region is extremely rare.^2,4 This condition is the result of chronic irritant dermatitis from frequent exposure to urine or feces, leading to maceration and epidermal hyperplasia. It occurs because of improper sizing of the stoma bag or incorrect positioning or construction of the stoma.⁵

the overuse of topical benzocaine-resorcinol, leading to chronic irritation.⁶ It is clinically characterized by multiple grayish-white, wartlike, confluent papulonodules around areas chronically exposed to moisture. Differential diagnoses such as secondary neoplasms, HPV infection, exuberant granulation tissue, and candidal infections should be considered.³ Final diagnosis is based on clinicopathologic findings, similar to our case. Epidermal growth factor and transforming growth factor are thought to play a role in the pathophysiology of pseudoepitheliomatous hyperplasia. Increased expression of these mediators leads to proliferation of the epidermis into the dermis.⁷ The role of HPV in PPN remains unclear, as not all PPN lesions are positive for HPV and the cutaneous lesions resolve once the source of irritation is removed. Recommended treatment includes local skin care; stoma refitting; and, in severe cases, excision and revision of the stoma.² Dermatologists must be aware of this often-underdiagnosed condition.

Dermatopathology education, which comprises approximately 30% of the dermatology residency curriculum, is crucial for the holistic training of dermatology residents to diagnose and manage a range of dermatologic conditions.¹ Additionally, dermatopathology is the topic of one of the 4 American Board of Dermatology CORE Exam modules, further highlighting the need for comprehensive education in this area. A variety of resources including virtual dermatopathology and conventional microscopy training currently are used in residency programs for dermatopathology education.^2,3 Although used less frequently, social media platforms such as Instagram also are used to aid in dermatopathology education for a wider audience.⁴ Other online resources, including the American Society of Dermatopathology website (www.asdp.org) and DermpathAtlas.com, are excellent tools for medical students, residents, and fellows to develop their knowledge.⁵ While these resources are accessible, they must be directly sought out by the student and utilized on their own time. Additionally, if medical students do not have a strong understanding of the basics of dermatopathology, they may not have the foundation required to benefit from these resources.

Dermatopathology education is critical for the overall practice of dermatology, yet most dermatology residency programs may not be incorporating dermatopathology education early enough in training. One study evaluating the timing and length of dermatopathology education during residency reported that fewer than 40% (20/51) of dermatology residency programs allocate 3 or more weeks to dermatopathology education during the second postgraduate year.¹ Despite Ackerman6 advocating for early dermatopathology exposure to best prepare medical students to recognize and manage certain dermatologic conditions, the majority of exposure still seems to occur during postgraduate year 4.¹ Furthermore, current primary care residents feel that their medical school training did not sufficiently prepare them to diagnose and manage dermatologic conditions, with only 37% (93/252) reporting feeling adequately prepared.^7,8 Medical students also reported a lack of confidence in overall dermatology knowledge, with 89% (72/81) reporting they felt neutral, slightly confident, or not at all confident when asked to diagnose skin lesions.⁹ In the same study, the average score was 46.6% (7/15 questions answered correctly) when 74 participants were assessed via a multiple choice quiz on dermatologic diagnosis and treatment, further demonstrating the lack of general dermatology comfort among medical students.⁹ This likely stems from limited dermatology curriculum in medical schools, demonstrating the need for further dermatology education as a whole in medical school.¹⁰

Ensuring robust dermatopathology education in medical school and the first year of dermatology residency has the potential to better prepare medical students for the transition into dermatology residency and clinical practice. We created an introductory dermatopathology lecture and presented it to medical students and first year dermatology residents to improve dermatopathology knowledge and confidence in learners early in their dermatology training.

Structure of the Lecture

Participants included first-year dermatology residents and fourth-year medical students rotating with the Wayne State University Department of Dermatology (Detroit, Michigan). The same facilitator (H.O.) taught each of the lectures, and all lectures were conducted via Zoom at the beginning of the month from May 2024 through November 2024. A total of 7 lectures were given. The lecture was formatted so that a histologic image was shown, then learners expressed their thoughts about what the image was showing before the answer was given. This format allowed participants to view the images on their own device screen and allowed the facilitator to annotate the images. The lecture was divided into 3 sections: (1) cell types and basic structures, (2) anatomic slides, and (3) common diagnoses. Each session lasted approximately 45 minutes.

Section 1: Cell Types and Basic Structures—The first section covered the fundamental cell types (neutrophils, lymphocytes, plasma cells, melanocytes, and eosinophils) along with glandular structures (apocrine, eccrine, and sebaceous). The session was designed to follow a retention and allow learners to think through each slide. First, participants were shown histologic images of each cell type and were asked to identify what type of cell was being shown. On the following slide, key features of each cell type were highlighted. Next, participants similarly were shown images of the glandular structures followed by key features of each. The section concluded with a review of the layers of the skin (stratum corneum, stratum granulosum, stratum lucidum, stratum spinosum, and stratum basale). A histologic image was shown, and the facilitator discussed how to distinguish the layers.

Section 2: Anatomic Sites—This section focused on key pathologic features for differentiating body surfaces, including the scalp, face, eyelids, ears, areolae, palms and soles, and mucosae. Participants initially were shown an image of a hematoxylin and eosin–stained slide from a specific body surface and then were asked to identify structures that may serve as a clue to the anatomic location. If the participants were not sure, they were given hints; for example, when participants were shown an image of the ear and were unsure of the location, the facilitator circled cartilage and asked them to identify the structure. In most cases, once participants named this structure, they were able to recognize that the location was the ear.

Section 3: Common Diagnoses—This section addressed frequently encountered diagnoses in dermatopathology, including basal cell carcinoma, squamous cell carcinoma, squamous cell carcinoma in situ, epidermoid cyst, pilar cyst, seborrheic keratosis, solar lentigo, melanocytic nevus, melanoma, verruca vulgaris, spongiotic dermatitis, psoriasis, and lichen planus. It followed the same format of the first section: participants were shown an hemotoxyllin and eosin–stained image and then were asked to discuss what the diagnosis could be and why. Hints were given if participants struggled to come up with the correct diagnosis. A few slides also were dedicated to distinguishing benign nevi, dysplastic nevi, and melanoma.

Pretest and Posttest Results

Residents participated in the lecture as part of their first-year orientation, and medical students participated during their dermatology rotation. All participants were invited to complete a pretest and a posttest before and after the lecture, respectively. Both assessments were optional and anonymous. The pretest was completed electronically and consisted of 10 knowledge-based, multiple-choice questions that included a histopathologic image and asked, “What is the most likely diagnosis?,” “What is the predominant cell type?,” and “Where was this specimen taken from?” In addition to the knowledge-based questions, participants also were asked to rate their confidence in dermatopathology on a 5-point Likert scale ranging from 1 (not confident at all) to 5 (extremely confident). Participants completed the entire pretest before any information on the topic was provided. After the lecture, participants were asked to complete a posttest identical to the pretest and to rate their confidence in dermatopathology again on the same scale. The posttest included an additional question asking participants to rate the helpfulness of the lecture on a Likert scale ranging from 1 (not helpful at all) to 5 (extremely helpful). Participants completed the posttest within 48 hours of the lecture.

Overall, 15 learners participated in the pretest and 12 in the posttest. Of the 15 pretest participants, 3 were first-year residents and 12 were medical students. Similarly, in the posttest, 2 respondents were first-year residents and 10 were medical students. All responses contained complete pretests and posttests. The mean score on the pretest was 62%, whereas the mean score on the posttest was 75%. A paired t test indicated a statistically significant improvement (P=.017). In addition, the mean rating for confidence in dermatopathology knowledge before the lecture was 1.5 prior to the lecture and 2.6 after the lecture. A paired t test demonstrated statistical significance (P=.010). The mean rating of the helpfulness of the lecture was 4.67. The majority (91.7% [11/12]) of the participants gave a rating of 4 or 5.

Impact of the Lecture on Dermatopathology Knowledge

There is a gap in dermatopathology education early in medical training. Our introductory lecture led to higher post test scores and increased confidence in dermatopathology among medical students and dermatology residents, demonstrating the effectiveness of this kind of program in bridging this education gap. The majority of participants in our lecture said they found the session helpful. A previously published article called for early implementation of dermatology education as a whole in the medical curriculum due to lack of knowledge and confidence, and our introductory lecture may help to bridge this gap.⁸ Increasing dermatopathology content for medical students and first-year dermatology residents can expand knowledge, as shown by the increased scores on the posttest, and better supports learners transitioning to dermatology residency, where dermatopathology constitutes a large part of the overall curriculum.² More comprehensive knowledge of dermatopathology early in dermatology training also may help to better prepare residents to accurately diagnose and manage dermatologic conditions.

Pretest scores showed that the average confidence rating in dermatopathology among participants in our lecture was 1.5, which is rather low. This is consistent with prior studies that have found that residents feel that medical school inadequately prepared them for dermatology residency.^7,8 More than 87% (71/81) of medical students surveyed felt they received inadequate general dermatology training in medical school.⁹ This supports the proposed educational gap that is impacting confidence in overall dermatology knowledge, which includes dermatopathology. In our study, the average confidence rating increased by 1.1 points after the lecture, which was statistically significant (P=.010) and demonstrates that an introductory lecture serves as a feasible intervention to improve confidence in this area.

The feedback we received from participants in our lecture shows the benefits of an introductory interactive lecture with virtual dermatopathology images. Ngo et al2 highlighted how residents perceive virtual images to be superior to conventional microscopy for dermatopathology, which we utilized in our lecture. This method is not only cost effective but also provides a simple way for learners and facilitators to point out key findings on histopathology slides.²

Final Thoughts

Overall, implementing dermatopathology education early in training has a measurable impact on dermatopathology knowledge and confidence among medical students and first-year dermatology residents. An interactive lecture with virtual images similar to the one we describe here may better prepare learners for the transition to dermatology residency by addressing the educational gap in dermatopathology early in training.

Dermatopathology education, which comprises approximately 30% of the dermatology residency curriculum, is crucial for the holistic training of dermatology residents to diagnose and manage a range of dermatologic conditions.¹ Additionally, dermatopathology is the topic of one of the 4 American Board of Dermatology CORE Exam modules, further highlighting the need for comprehensive education in this area. A variety of resources including virtual dermatopathology and conventional microscopy training currently are used in residency programs for dermatopathology education.^2,3 Although used less frequently, social media platforms such as Instagram also are used to aid in dermatopathology education for a wider audience.⁴ Other online resources, including the American Society of Dermatopathology website (www.asdp.org) and DermpathAtlas.com, are excellent tools for medical students, residents, and fellows to develop their knowledge.⁵ While these resources are accessible, they must be directly sought out by the student and utilized on their own time. Additionally, if medical students do not have a strong understanding of the basics of dermatopathology, they may not have the foundation required to benefit from these resources.

Dermatopathology education is critical for the overall practice of dermatology, yet most dermatology residency programs may not be incorporating dermatopathology education early enough in training. One study evaluating the timing and length of dermatopathology education during residency reported that fewer than 40% (20/51) of dermatology residency programs allocate 3 or more weeks to dermatopathology education during the second postgraduate year.¹ Despite Ackerman6 advocating for early dermatopathology exposure to best prepare medical students to recognize and manage certain dermatologic conditions, the majority of exposure still seems to occur during postgraduate year 4.¹ Furthermore, current primary care residents feel that their medical school training did not sufficiently prepare them to diagnose and manage dermatologic conditions, with only 37% (93/252) reporting feeling adequately prepared.^7,8 Medical students also reported a lack of confidence in overall dermatology knowledge, with 89% (72/81) reporting they felt neutral, slightly confident, or not at all confident when asked to diagnose skin lesions.⁹ In the same study, the average score was 46.6% (7/15 questions answered correctly) when 74 participants were assessed via a multiple choice quiz on dermatologic diagnosis and treatment, further demonstrating the lack of general dermatology comfort among medical students.⁹ This likely stems from limited dermatology curriculum in medical schools, demonstrating the need for further dermatology education as a whole in medical school.¹⁰

Ensuring robust dermatopathology education in medical school and the first year of dermatology residency has the potential to better prepare medical students for the transition into dermatology residency and clinical practice. We created an introductory dermatopathology lecture and presented it to medical students and first year dermatology residents to improve dermatopathology knowledge and confidence in learners early in their dermatology training.

Structure of the Lecture

Participants included first-year dermatology residents and fourth-year medical students rotating with the Wayne State University Department of Dermatology (Detroit, Michigan). The same facilitator (H.O.) taught each of the lectures, and all lectures were conducted via Zoom at the beginning of the month from May 2024 through November 2024. A total of 7 lectures were given. The lecture was formatted so that a histologic image was shown, then learners expressed their thoughts about what the image was showing before the answer was given. This format allowed participants to view the images on their own device screen and allowed the facilitator to annotate the images. The lecture was divided into 3 sections: (1) cell types and basic structures, (2) anatomic slides, and (3) common diagnoses. Each session lasted approximately 45 minutes.

Section 1: Cell Types and Basic Structures—The first section covered the fundamental cell types (neutrophils, lymphocytes, plasma cells, melanocytes, and eosinophils) along with glandular structures (apocrine, eccrine, and sebaceous). The session was designed to follow a retention and allow learners to think through each slide. First, participants were shown histologic images of each cell type and were asked to identify what type of cell was being shown. On the following slide, key features of each cell type were highlighted. Next, participants similarly were shown images of the glandular structures followed by key features of each. The section concluded with a review of the layers of the skin (stratum corneum, stratum granulosum, stratum lucidum, stratum spinosum, and stratum basale). A histologic image was shown, and the facilitator discussed how to distinguish the layers.

Section 2: Anatomic Sites—This section focused on key pathologic features for differentiating body surfaces, including the scalp, face, eyelids, ears, areolae, palms and soles, and mucosae. Participants initially were shown an image of a hematoxylin and eosin–stained slide from a specific body surface and then were asked to identify structures that may serve as a clue to the anatomic location. If the participants were not sure, they were given hints; for example, when participants were shown an image of the ear and were unsure of the location, the facilitator circled cartilage and asked them to identify the structure. In most cases, once participants named this structure, they were able to recognize that the location was the ear.

Section 3: Common Diagnoses—This section addressed frequently encountered diagnoses in dermatopathology, including basal cell carcinoma, squamous cell carcinoma, squamous cell carcinoma in situ, epidermoid cyst, pilar cyst, seborrheic keratosis, solar lentigo, melanocytic nevus, melanoma, verruca vulgaris, spongiotic dermatitis, psoriasis, and lichen planus. It followed the same format of the first section: participants were shown an hemotoxyllin and eosin–stained image and then were asked to discuss what the diagnosis could be and why. Hints were given if participants struggled to come up with the correct diagnosis. A few slides also were dedicated to distinguishing benign nevi, dysplastic nevi, and melanoma.

Pretest and Posttest Results

Residents participated in the lecture as part of their first-year orientation, and medical students participated during their dermatology rotation. All participants were invited to complete a pretest and a posttest before and after the lecture, respectively. Both assessments were optional and anonymous. The pretest was completed electronically and consisted of 10 knowledge-based, multiple-choice questions that included a histopathologic image and asked, “What is the most likely diagnosis?,” “What is the predominant cell type?,” and “Where was this specimen taken from?” In addition to the knowledge-based questions, participants also were asked to rate their confidence in dermatopathology on a 5-point Likert scale ranging from 1 (not confident at all) to 5 (extremely confident). Participants completed the entire pretest before any information on the topic was provided. After the lecture, participants were asked to complete a posttest identical to the pretest and to rate their confidence in dermatopathology again on the same scale. The posttest included an additional question asking participants to rate the helpfulness of the lecture on a Likert scale ranging from 1 (not helpful at all) to 5 (extremely helpful). Participants completed the posttest within 48 hours of the lecture.

Overall, 15 learners participated in the pretest and 12 in the posttest. Of the 15 pretest participants, 3 were first-year residents and 12 were medical students. Similarly, in the posttest, 2 respondents were first-year residents and 10 were medical students. All responses contained complete pretests and posttests. The mean score on the pretest was 62%, whereas the mean score on the posttest was 75%. A paired t test indicated a statistically significant improvement (P=.017). In addition, the mean rating for confidence in dermatopathology knowledge before the lecture was 1.5 prior to the lecture and 2.6 after the lecture. A paired t test demonstrated statistical significance (P=.010). The mean rating of the helpfulness of the lecture was 4.67. The majority (91.7% [11/12]) of the participants gave a rating of 4 or 5.

Impact of the Lecture on Dermatopathology Knowledge

There is a gap in dermatopathology education early in medical training. Our introductory lecture led to higher post test scores and increased confidence in dermatopathology among medical students and dermatology residents, demonstrating the effectiveness of this kind of program in bridging this education gap. The majority of participants in our lecture said they found the session helpful. A previously published article called for early implementation of dermatology education as a whole in the medical curriculum due to lack of knowledge and confidence, and our introductory lecture may help to bridge this gap.⁸ Increasing dermatopathology content for medical students and first-year dermatology residents can expand knowledge, as shown by the increased scores on the posttest, and better supports learners transitioning to dermatology residency, where dermatopathology constitutes a large part of the overall curriculum.² More comprehensive knowledge of dermatopathology early in dermatology training also may help to better prepare residents to accurately diagnose and manage dermatologic conditions.

Pretest scores showed that the average confidence rating in dermatopathology among participants in our lecture was 1.5, which is rather low. This is consistent with prior studies that have found that residents feel that medical school inadequately prepared them for dermatology residency.^7,8 More than 87% (71/81) of medical students surveyed felt they received inadequate general dermatology training in medical school.⁹ This supports the proposed educational gap that is impacting confidence in overall dermatology knowledge, which includes dermatopathology. In our study, the average confidence rating increased by 1.1 points after the lecture, which was statistically significant (P=.010) and demonstrates that an introductory lecture serves as a feasible intervention to improve confidence in this area.

The feedback we received from participants in our lecture shows the benefits of an introductory interactive lecture with virtual dermatopathology images. Ngo et al2 highlighted how residents perceive virtual images to be superior to conventional microscopy for dermatopathology, which we utilized in our lecture. This method is not only cost effective but also provides a simple way for learners and facilitators to point out key findings on histopathology slides.²

Final Thoughts

Overall, implementing dermatopathology education early in training has a measurable impact on dermatopathology knowledge and confidence among medical students and first-year dermatology residents. An interactive lecture with virtual images similar to the one we describe here may better prepare learners for the transition to dermatology residency by addressing the educational gap in dermatopathology early in training.

Dermatopathology education, which comprises approximately 30% of the dermatology residency curriculum, is crucial for the holistic training of dermatology residents to diagnose and manage a range of dermatologic conditions.¹ Additionally, dermatopathology is the topic of one of the 4 American Board of Dermatology CORE Exam modules, further highlighting the need for comprehensive education in this area. A variety of resources including virtual dermatopathology and conventional microscopy training currently are used in residency programs for dermatopathology education.^2,3 Although used less frequently, social media platforms such as Instagram also are used to aid in dermatopathology education for a wider audience.⁴ Other online resources, including the American Society of Dermatopathology website (www.asdp.org) and DermpathAtlas.com, are excellent tools for medical students, residents, and fellows to develop their knowledge.⁵ While these resources are accessible, they must be directly sought out by the student and utilized on their own time. Additionally, if medical students do not have a strong understanding of the basics of dermatopathology, they may not have the foundation required to benefit from these resources.

Dermatopathology education is critical for the overall practice of dermatology, yet most dermatology residency programs may not be incorporating dermatopathology education early enough in training. One study evaluating the timing and length of dermatopathology education during residency reported that fewer than 40% (20/51) of dermatology residency programs allocate 3 or more weeks to dermatopathology education during the second postgraduate year.¹ Despite Ackerman6 advocating for early dermatopathology exposure to best prepare medical students to recognize and manage certain dermatologic conditions, the majority of exposure still seems to occur during postgraduate year 4.¹ Furthermore, current primary care residents feel that their medical school training did not sufficiently prepare them to diagnose and manage dermatologic conditions, with only 37% (93/252) reporting feeling adequately prepared.^7,8 Medical students also reported a lack of confidence in overall dermatology knowledge, with 89% (72/81) reporting they felt neutral, slightly confident, or not at all confident when asked to diagnose skin lesions.⁹ In the same study, the average score was 46.6% (7/15 questions answered correctly) when 74 participants were assessed via a multiple choice quiz on dermatologic diagnosis and treatment, further demonstrating the lack of general dermatology comfort among medical students.⁹ This likely stems from limited dermatology curriculum in medical schools, demonstrating the need for further dermatology education as a whole in medical school.¹⁰

Ensuring robust dermatopathology education in medical school and the first year of dermatology residency has the potential to better prepare medical students for the transition into dermatology residency and clinical practice. We created an introductory dermatopathology lecture and presented it to medical students and first year dermatology residents to improve dermatopathology knowledge and confidence in learners early in their dermatology training.

Structure of the Lecture

Participants included first-year dermatology residents and fourth-year medical students rotating with the Wayne State University Department of Dermatology (Detroit, Michigan). The same facilitator (H.O.) taught each of the lectures, and all lectures were conducted via Zoom at the beginning of the month from May 2024 through November 2024. A total of 7 lectures were given. The lecture was formatted so that a histologic image was shown, then learners expressed their thoughts about what the image was showing before the answer was given. This format allowed participants to view the images on their own device screen and allowed the facilitator to annotate the images. The lecture was divided into 3 sections: (1) cell types and basic structures, (2) anatomic slides, and (3) common diagnoses. Each session lasted approximately 45 minutes.

Section 1: Cell Types and Basic Structures—The first section covered the fundamental cell types (neutrophils, lymphocytes, plasma cells, melanocytes, and eosinophils) along with glandular structures (apocrine, eccrine, and sebaceous). The session was designed to follow a retention and allow learners to think through each slide. First, participants were shown histologic images of each cell type and were asked to identify what type of cell was being shown. On the following slide, key features of each cell type were highlighted. Next, participants similarly were shown images of the glandular structures followed by key features of each. The section concluded with a review of the layers of the skin (stratum corneum, stratum granulosum, stratum lucidum, stratum spinosum, and stratum basale). A histologic image was shown, and the facilitator discussed how to distinguish the layers.

Section 2: Anatomic Sites—This section focused on key pathologic features for differentiating body surfaces, including the scalp, face, eyelids, ears, areolae, palms and soles, and mucosae. Participants initially were shown an image of a hematoxylin and eosin–stained slide from a specific body surface and then were asked to identify structures that may serve as a clue to the anatomic location. If the participants were not sure, they were given hints; for example, when participants were shown an image of the ear and were unsure of the location, the facilitator circled cartilage and asked them to identify the structure. In most cases, once participants named this structure, they were able to recognize that the location was the ear.

Section 3: Common Diagnoses—This section addressed frequently encountered diagnoses in dermatopathology, including basal cell carcinoma, squamous cell carcinoma, squamous cell carcinoma in situ, epidermoid cyst, pilar cyst, seborrheic keratosis, solar lentigo, melanocytic nevus, melanoma, verruca vulgaris, spongiotic dermatitis, psoriasis, and lichen planus. It followed the same format of the first section: participants were shown an hemotoxyllin and eosin–stained image and then were asked to discuss what the diagnosis could be and why. Hints were given if participants struggled to come up with the correct diagnosis. A few slides also were dedicated to distinguishing benign nevi, dysplastic nevi, and melanoma.

Pretest and Posttest Results

Residents participated in the lecture as part of their first-year orientation, and medical students participated during their dermatology rotation. All participants were invited to complete a pretest and a posttest before and after the lecture, respectively. Both assessments were optional and anonymous. The pretest was completed electronically and consisted of 10 knowledge-based, multiple-choice questions that included a histopathologic image and asked, “What is the most likely diagnosis?,” “What is the predominant cell type?,” and “Where was this specimen taken from?” In addition to the knowledge-based questions, participants also were asked to rate their confidence in dermatopathology on a 5-point Likert scale ranging from 1 (not confident at all) to 5 (extremely confident). Participants completed the entire pretest before any information on the topic was provided. After the lecture, participants were asked to complete a posttest identical to the pretest and to rate their confidence in dermatopathology again on the same scale. The posttest included an additional question asking participants to rate the helpfulness of the lecture on a Likert scale ranging from 1 (not helpful at all) to 5 (extremely helpful). Participants completed the posttest within 48 hours of the lecture.

Overall, 15 learners participated in the pretest and 12 in the posttest. Of the 15 pretest participants, 3 were first-year residents and 12 were medical students. Similarly, in the posttest, 2 respondents were first-year residents and 10 were medical students. All responses contained complete pretests and posttests. The mean score on the pretest was 62%, whereas the mean score on the posttest was 75%. A paired t test indicated a statistically significant improvement (P=.017). In addition, the mean rating for confidence in dermatopathology knowledge before the lecture was 1.5 prior to the lecture and 2.6 after the lecture. A paired t test demonstrated statistical significance (P=.010). The mean rating of the helpfulness of the lecture was 4.67. The majority (91.7% [11/12]) of the participants gave a rating of 4 or 5.

Impact of the Lecture on Dermatopathology Knowledge

There is a gap in dermatopathology education early in medical training. Our introductory lecture led to higher post test scores and increased confidence in dermatopathology among medical students and dermatology residents, demonstrating the effectiveness of this kind of program in bridging this education gap. The majority of participants in our lecture said they found the session helpful. A previously published article called for early implementation of dermatology education as a whole in the medical curriculum due to lack of knowledge and confidence, and our introductory lecture may help to bridge this gap.⁸ Increasing dermatopathology content for medical students and first-year dermatology residents can expand knowledge, as shown by the increased scores on the posttest, and better supports learners transitioning to dermatology residency, where dermatopathology constitutes a large part of the overall curriculum.² More comprehensive knowledge of dermatopathology early in dermatology training also may help to better prepare residents to accurately diagnose and manage dermatologic conditions.

Pretest scores showed that the average confidence rating in dermatopathology among participants in our lecture was 1.5, which is rather low. This is consistent with prior studies that have found that residents feel that medical school inadequately prepared them for dermatology residency.^7,8 More than 87% (71/81) of medical students surveyed felt they received inadequate general dermatology training in medical school.⁹ This supports the proposed educational gap that is impacting confidence in overall dermatology knowledge, which includes dermatopathology. In our study, the average confidence rating increased by 1.1 points after the lecture, which was statistically significant (P=.010) and demonstrates that an introductory lecture serves as a feasible intervention to improve confidence in this area.

The feedback we received from participants in our lecture shows the benefits of an introductory interactive lecture with virtual dermatopathology images. Ngo et al2 highlighted how residents perceive virtual images to be superior to conventional microscopy for dermatopathology, which we utilized in our lecture. This method is not only cost effective but also provides a simple way for learners and facilitators to point out key findings on histopathology slides.²

Final Thoughts

Overall, implementing dermatopathology education early in training has a measurable impact on dermatopathology knowledge and confidence among medical students and first-year dermatology residents. An interactive lecture with virtual images similar to the one we describe here may better prepare learners for the transition to dermatology residency by addressing the educational gap in dermatopathology early in training.

THE DIAGNOSIS: Cutaneous Endometriosis

Endometriosis is the ectopic presence of endometrial tissue and occurs in approximately 13% of women of childbearing age.¹ This non-neoplastic lesion can manifest on the skin in less than 5.5% of endometriosis cases worldwide. Historically, secondary cutaneous endometriosis (CE) most frequently has been associated with prior gynecologic surgery (often cesarean section)²; however, an increased incidence of primary CE in patients without prior surgical history recently has been documented in the literature.³ While secondary CE usually manifests at the site of a surgical scar, primary CE has a predilection for the umbilicus (Villar nodule). In both primary and secondary CE, patients present clinically with a solitary nodule and abdominal pain that may be exacerbated during menstruation. Bleeding without associated pain may be more common in primary CE, while bleeding with pain may be more common in secondary CE. Cutaneous endometriosis often is overlooked given its low incidence, leading to delayed diagnosis. Primary CE often is misdiagnosed clinically as a pyogenic granuloma, Sister Mary Joseph nodule, or keloid, while secondary CE may be mistaken for a fibroma, incisional hernia, or granuloma.²

Primary and secondary CE have identical histopathologic features. Glands of variable size consisting of a single epithelial layer of columnar cells are present in the reticular dermis or subcutis (quiz image).⁴ The accompanying periglandular stroma often is uniform, consisting of spindle-shaped basophilic cells with abundant vascular structures. The stroma may contain moderate numbers of mitotic figures, a chronic inflammatory infiltrate, and extravasated red blood cells. The ectopic tissue may be inactive or display morphologic changes resembling those of the endometrium in the normal menstrual cycle.⁴ As the ectopic tissue progresses through the stages of menstruation, the glandular morphology also transforms. The proliferative stage demonstrates increased epithelial mitotic figures, the secretory stage exhibits intraluminal secretion, and during menstruation there are degenerative epithelial cells and evidence of vascular congestion. A mixture of glandular stages may be seen in biopsy results. Robust immunohistochemical expression of CD10 in the endometrial stroma can aid in diagnosis (Figure 1). Estrogen and progesterone receptor immunostaining also shows strong nuclear positivity, except in decidualized tissue.⁴ Unlike intestinal glands, endometrial glands do not express CDX2 or CK20.⁵ Complete surgical excision of CE usually is curative; however, recurrence has been documented in 10% (3/30) of cases.²

Breast carcinoma is the most common internal malignancy associated with cutaneous metastasis and may develop prior to visceral diagnosis. It is possible that tumor cells travel through the communicating networks of the cutaneous lymphatic ducts and the mammary lymphatic plexus; however, cutaneous manifestation often is located on the ipsilateral breast, and therefore tumor expansion rather than true metastasis cannot always be ruled out. On histopathology, findings of breast adenocarcinoma include tumor cells that tend to show either interstitial, nodular, mixed, or intravascular growth patterns (Figure 2). Tumor cells may invade the stroma in clusters or as individual cells. Sites of distant metastasis may show an increased likelihood of vascular and lymphatic invasion.⁶

Nodular hidradenoma often manifests as a solitary nodule in the head or neck region, predominantly in women.⁷ Pathology shows well-demarcated intradermal aggregates of tumor cells within a hyalinized stroma; connection to the epidermis is not a feature of nodular hidradenoma. The epithelial component consists of polygonal cells with eosinophilic to amphophilic cytoplasm as well as large glycogenated cells with pale to clear cytoplasm (leading to the alternative term clear cell hidradenoma)(Figure 3). The cystic portion represents deterioration of tumor cells. Surgical excision usually is curative, although lesions may recur. Malignant transformation is rare.⁷

Sister Mary Joseph nodule is a cutaneous involvement of the umbilicus by a metastatic malignancy, often from an intra-abdominal primary malignancy (most commonly ovarian carcinoma in women and colonic carcinoma in men). Clinically, patients present with a solitary firm nodule or plaque within the umbilicus.^8,9 Histopathology recapitulates the primary tumor (Figure 4).⁹ Sister Mary Joseph nodule portends a poor prognosis, with a survival rate of less than 8 months from the time of diagnosis.¹⁰

Urachal duct cyst develops from a remnant of the urachus that closed appropriately at the umbilicus and bladder but did not completely regress. It may manifest as an extraperitoneal mass at the umbilicus. Clinically, urachal duct cysts may be asymptomatic until an inciting event (eg, inflammation, deposition of calculus, or malignancy) occurs.¹¹ Histopathology shows cystically dilated structures lined with a transitional epithelium (Figure 5).¹² Urachal duct cysts usually are diagnosed in children or young adults and subsequently are excised.¹¹

THE DIAGNOSIS: Cutaneous Endometriosis

Endometriosis is the ectopic presence of endometrial tissue and occurs in approximately 13% of women of childbearing age.¹ This non-neoplastic lesion can manifest on the skin in less than 5.5% of endometriosis cases worldwide. Historically, secondary cutaneous endometriosis (CE) most frequently has been associated with prior gynecologic surgery (often cesarean section)²; however, an increased incidence of primary CE in patients without prior surgical history recently has been documented in the literature.³ While secondary CE usually manifests at the site of a surgical scar, primary CE has a predilection for the umbilicus (Villar nodule). In both primary and secondary CE, patients present clinically with a solitary nodule and abdominal pain that may be exacerbated during menstruation. Bleeding without associated pain may be more common in primary CE, while bleeding with pain may be more common in secondary CE. Cutaneous endometriosis often is overlooked given its low incidence, leading to delayed diagnosis. Primary CE often is misdiagnosed clinically as a pyogenic granuloma, Sister Mary Joseph nodule, or keloid, while secondary CE may be mistaken for a fibroma, incisional hernia, or granuloma.²

Primary and secondary CE have identical histopathologic features. Glands of variable size consisting of a single epithelial layer of columnar cells are present in the reticular dermis or subcutis (quiz image).⁴ The accompanying periglandular stroma often is uniform, consisting of spindle-shaped basophilic cells with abundant vascular structures. The stroma may contain moderate numbers of mitotic figures, a chronic inflammatory infiltrate, and extravasated red blood cells. The ectopic tissue may be inactive or display morphologic changes resembling those of the endometrium in the normal menstrual cycle.⁴ As the ectopic tissue progresses through the stages of menstruation, the glandular morphology also transforms. The proliferative stage demonstrates increased epithelial mitotic figures, the secretory stage exhibits intraluminal secretion, and during menstruation there are degenerative epithelial cells and evidence of vascular congestion. A mixture of glandular stages may be seen in biopsy results. Robust immunohistochemical expression of CD10 in the endometrial stroma can aid in diagnosis (Figure 1). Estrogen and progesterone receptor immunostaining also shows strong nuclear positivity, except in decidualized tissue.⁴ Unlike intestinal glands, endometrial glands do not express CDX2 or CK20.⁵ Complete surgical excision of CE usually is curative; however, recurrence has been documented in 10% (3/30) of cases.²

Breast carcinoma is the most common internal malignancy associated with cutaneous metastasis and may develop prior to visceral diagnosis. It is possible that tumor cells travel through the communicating networks of the cutaneous lymphatic ducts and the mammary lymphatic plexus; however, cutaneous manifestation often is located on the ipsilateral breast, and therefore tumor expansion rather than true metastasis cannot always be ruled out. On histopathology, findings of breast adenocarcinoma include tumor cells that tend to show either interstitial, nodular, mixed, or intravascular growth patterns (Figure 2). Tumor cells may invade the stroma in clusters or as individual cells. Sites of distant metastasis may show an increased likelihood of vascular and lymphatic invasion.⁶

Nodular hidradenoma often manifests as a solitary nodule in the head or neck region, predominantly in women.⁷ Pathology shows well-demarcated intradermal aggregates of tumor cells within a hyalinized stroma; connection to the epidermis is not a feature of nodular hidradenoma. The epithelial component consists of polygonal cells with eosinophilic to amphophilic cytoplasm as well as large glycogenated cells with pale to clear cytoplasm (leading to the alternative term clear cell hidradenoma)(Figure 3). The cystic portion represents deterioration of tumor cells. Surgical excision usually is curative, although lesions may recur. Malignant transformation is rare.⁷

Sister Mary Joseph nodule is a cutaneous involvement of the umbilicus by a metastatic malignancy, often from an intra-abdominal primary malignancy (most commonly ovarian carcinoma in women and colonic carcinoma in men). Clinically, patients present with a solitary firm nodule or plaque within the umbilicus.^8,9 Histopathology recapitulates the primary tumor (Figure 4).⁹ Sister Mary Joseph nodule portends a poor prognosis, with a survival rate of less than 8 months from the time of diagnosis.¹⁰

Urachal duct cyst develops from a remnant of the urachus that closed appropriately at the umbilicus and bladder but did not completely regress. It may manifest as an extraperitoneal mass at the umbilicus. Clinically, urachal duct cysts may be asymptomatic until an inciting event (eg, inflammation, deposition of calculus, or malignancy) occurs.¹¹ Histopathology shows cystically dilated structures lined with a transitional epithelium (Figure 5).¹² Urachal duct cysts usually are diagnosed in children or young adults and subsequently are excised.¹¹

THE DIAGNOSIS: Cutaneous Endometriosis

Endometriosis is the ectopic presence of endometrial tissue and occurs in approximately 13% of women of childbearing age.¹ This non-neoplastic lesion can manifest on the skin in less than 5.5% of endometriosis cases worldwide. Historically, secondary cutaneous endometriosis (CE) most frequently has been associated with prior gynecologic surgery (often cesarean section)²; however, an increased incidence of primary CE in patients without prior surgical history recently has been documented in the literature.³ While secondary CE usually manifests at the site of a surgical scar, primary CE has a predilection for the umbilicus (Villar nodule). In both primary and secondary CE, patients present clinically with a solitary nodule and abdominal pain that may be exacerbated during menstruation. Bleeding without associated pain may be more common in primary CE, while bleeding with pain may be more common in secondary CE. Cutaneous endometriosis often is overlooked given its low incidence, leading to delayed diagnosis. Primary CE often is misdiagnosed clinically as a pyogenic granuloma, Sister Mary Joseph nodule, or keloid, while secondary CE may be mistaken for a fibroma, incisional hernia, or granuloma.²

Primary and secondary CE have identical histopathologic features. Glands of variable size consisting of a single epithelial layer of columnar cells are present in the reticular dermis or subcutis (quiz image).⁴ The accompanying periglandular stroma often is uniform, consisting of spindle-shaped basophilic cells with abundant vascular structures. The stroma may contain moderate numbers of mitotic figures, a chronic inflammatory infiltrate, and extravasated red blood cells. The ectopic tissue may be inactive or display morphologic changes resembling those of the endometrium in the normal menstrual cycle.⁴ As the ectopic tissue progresses through the stages of menstruation, the glandular morphology also transforms. The proliferative stage demonstrates increased epithelial mitotic figures, the secretory stage exhibits intraluminal secretion, and during menstruation there are degenerative epithelial cells and evidence of vascular congestion. A mixture of glandular stages may be seen in biopsy results. Robust immunohistochemical expression of CD10 in the endometrial stroma can aid in diagnosis (Figure 1). Estrogen and progesterone receptor immunostaining also shows strong nuclear positivity, except in decidualized tissue.⁴ Unlike intestinal glands, endometrial glands do not express CDX2 or CK20.⁵ Complete surgical excision of CE usually is curative; however, recurrence has been documented in 10% (3/30) of cases.²

Breast carcinoma is the most common internal malignancy associated with cutaneous metastasis and may develop prior to visceral diagnosis. It is possible that tumor cells travel through the communicating networks of the cutaneous lymphatic ducts and the mammary lymphatic plexus; however, cutaneous manifestation often is located on the ipsilateral breast, and therefore tumor expansion rather than true metastasis cannot always be ruled out. On histopathology, findings of breast adenocarcinoma include tumor cells that tend to show either interstitial, nodular, mixed, or intravascular growth patterns (Figure 2). Tumor cells may invade the stroma in clusters or as individual cells. Sites of distant metastasis may show an increased likelihood of vascular and lymphatic invasion.⁶

Nodular hidradenoma often manifests as a solitary nodule in the head or neck region, predominantly in women.⁷ Pathology shows well-demarcated intradermal aggregates of tumor cells within a hyalinized stroma; connection to the epidermis is not a feature of nodular hidradenoma. The epithelial component consists of polygonal cells with eosinophilic to amphophilic cytoplasm as well as large glycogenated cells with pale to clear cytoplasm (leading to the alternative term clear cell hidradenoma)(Figure 3). The cystic portion represents deterioration of tumor cells. Surgical excision usually is curative, although lesions may recur. Malignant transformation is rare.⁷

Sister Mary Joseph nodule is a cutaneous involvement of the umbilicus by a metastatic malignancy, often from an intra-abdominal primary malignancy (most commonly ovarian carcinoma in women and colonic carcinoma in men). Clinically, patients present with a solitary firm nodule or plaque within the umbilicus.^8,9 Histopathology recapitulates the primary tumor (Figure 4).⁹ Sister Mary Joseph nodule portends a poor prognosis, with a survival rate of less than 8 months from the time of diagnosis.¹⁰

Urachal duct cyst develops from a remnant of the urachus that closed appropriately at the umbilicus and bladder but did not completely regress. It may manifest as an extraperitoneal mass at the umbilicus. Clinically, urachal duct cysts may be asymptomatic until an inciting event (eg, inflammation, deposition of calculus, or malignancy) occurs.¹¹ Histopathology shows cystically dilated structures lined with a transitional epithelium (Figure 5).¹² Urachal duct cysts usually are diagnosed in children or young adults and subsequently are excised.¹¹

Alpha-gal syndrome (AGS), a tickborne disease commonly called “red meat allergy,” is a serious, potentially life-threatening allergy to the carbohydrate alpha-gal. The alpha-gal carbohydrate is found in most mammals, though it is not in humans, apes, or old-world monkeys. People with AGS can have allergic reactions when they consume mammalian meat, dairy products, or other products derived from mammals. People often live with this disease for years before receiving a correct diagnosis, greatly impacting their quality of life. The number of suspected cases is also rising. 

More than 110,000 suspected AGS cases were identified between 2010 and 2022, according to a Centers for Disease Control and Prevention (CDC) report.¹ However, because the diagnosis requires a positive test and a clinical exam and some people may not get tested, as many as 450,000 people might be affected by AGS in the United States. Additionally, a CDC survey found that nearly half (42%) of US healthcare providers had never heard of AGS.² Among those who had, less than one third (29%) knew how to diagnose the condition. 

Here are 5 things clinicians need to know about AGS.

 

1. People can develop AGS after being bitten by a tick, primarily the lone star tick (Amblyomma americanum), in the United States.

In the United States, AGS is primarily associated with the bite of a lone star tick, but other kinds of ticks have not been ruled out. The majority of suspected AGS cases in the United States were reported in parts of Arkansas, Delaware, Illinois, Indiana, Kansas, Kentucky, Maryland, Mississippi, Missouri, North Carolina, Oklahoma, Tennessee, and Virginia. The lone star tick is widely distributed with established populations in Alabama, Arkansas, Connecticut, Delaware, Florida, Georgia, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Michigan, Minnesota, Mississippi, Missouri, Nebraska, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, and West Virginia. 

While AGS is associated with tick bites, more research is needed to understand the role ticks play in starting this condition, and why certain people develop AGS. Anyone can develop AGS, but most cases have been reported in adults. 

Know how to recognize the symptoms of AGS and be prepared to test, diagnose, and manage AGS, particularly in states where lone star ticks are found. 

 

2. Tick bites are only one risk factor for developing AGS. 

Many people are bitten by lone star ticks and will never develop AGS. Scientists are exploring the connection between other risk factors and developing AGS. A recent study has shown that people diagnosed with AGS may be more likely to have a family member who was also diagnosed with AGS, have another food allergy, have an allergy to stinging or biting insects, or have A or O blood types.³ 

Research has also shown that environmental risk factors could contribute to developing AGS,⁴ like living in an area with lone star ticks, remembering finding a tick on themselves, recalling multiple tick bites, living near a wooded forest, spending more time outside, or living in areas with deer, such as larger properties, wooded forests, and properties with shrubs and brush. 

Ask your patient questions about other allergies and history of recent tick bites or outdoor exposure to help determine if testing for AGS is appropriate.

 

3. Symptoms of AGS are consistently inconsistent.

There is a spectrum of how sensitive AGS patients are to alpha-gal, and reactions are often different from person to person, which can make it difficult to diagnose. The first allergic reaction to AGS typically occurs between 1-6 months after a tick bite. Symptoms commonly appear 2-6 hours after being in contact with products containing alpha-gal, like red meat (beef, pork, lamb, venison, rabbit, or other meat from mammals), dairy, and some medications. Symptoms can range from mild to severe and include hives or itchy rash; swelling of the lips, throat, tongue, or eyelids; gastrointestinal symptoms such as nausea, vomiting, or diarrhea; heartburn or indigestion; cough, shortness of breath, or difficulty breathing; dizziness or a drop in blood pressure; or anaphylaxis.

Consider AGS if a patient reports waking up in the middle of the night with allergic symptoms after eating alpha-gal containing products for dinner, if allergic reactions are delayed, or if a patient has anaphylaxis of unknown cause, adult-onset allergy, or allergic symptoms and reports a recent tick bite. 

 

4. Diagnosing AGS requires a combination of a blood test and a physical exam.

Diagnosing AGS requires a detailed patient history, physical exam, and a blood test to detect specific immunoglobulin E (IgE) antibodies specific to alpha-gal (alpha-gal sIgE). Tests for alpha-gal sIgE antibodies are available at several large commercial laboratories and some academic institutions. Skin tests to identify reactions to allergens like pork or beef may also be used to inform AGS diagnosis. However, a positive alpha-gal sIgE test or skin test does not mean a person has AGS. Many people, particularly those who live in regions with lone star ticks, have positive alpha-gal specific IgE tests without having AGS. 

Consider the test results along with your patient’s symptoms and risk factors.

 

5. There is no treatment for AGS, but people can take prevention steps and AGS can be managed.

People can protect themselves and their family from AGS by preventing tick bites. Encourage your patients to use an Environmental Protection Agency–registered insect repellent outdoors, wear permethrin-treated clothing, and conduct thorough tick checks after outdoor activities. 

Once a person is no longer exposed to alpha-gal containing products, they should no longer experience symptoms. People with AGS should also proactively prevent tick bites. Tick bites can trigger or reactivate AGS.

For patients who have AGS, help manage their symptoms and identify alpha-gal containing products to avoid.

Dr. Kersh is Chief of the Rickettsial Zoonoses Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, and disclosed no relevant conflicts of interest.

CDC resources:

About Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Testing and Diagnosis for Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Resources | Alpha-gal Syndrome | CDC 

References 

Thompson JM et al. MMWR Morb Mortal Wkly Rep. 2023;72:815-820. 

Carpenter A et al. MMWR Morb Mortal Wkly Rep. 2023;72:809-814. Taylor ML et al. Ann Allergy, Asthma & Immunol. 2024 Jun;132(6):759.e2-764.e2. Kersh GJ et al. Ann Allergy, Asthma & Immunol. 2023 Apr;130(4):472-478.

Alpha-gal syndrome (AGS), a tickborne disease commonly called “red meat allergy,” is a serious, potentially life-threatening allergy to the carbohydrate alpha-gal. The alpha-gal carbohydrate is found in most mammals, though it is not in humans, apes, or old-world monkeys. People with AGS can have allergic reactions when they consume mammalian meat, dairy products, or other products derived from mammals. People often live with this disease for years before receiving a correct diagnosis, greatly impacting their quality of life. The number of suspected cases is also rising. 

More than 110,000 suspected AGS cases were identified between 2010 and 2022, according to a Centers for Disease Control and Prevention (CDC) report.¹ However, because the diagnosis requires a positive test and a clinical exam and some people may not get tested, as many as 450,000 people might be affected by AGS in the United States. Additionally, a CDC survey found that nearly half (42%) of US healthcare providers had never heard of AGS.² Among those who had, less than one third (29%) knew how to diagnose the condition. 

Here are 5 things clinicians need to know about AGS.

 

1. People can develop AGS after being bitten by a tick, primarily the lone star tick (Amblyomma americanum), in the United States.

In the United States, AGS is primarily associated with the bite of a lone star tick, but other kinds of ticks have not been ruled out. The majority of suspected AGS cases in the United States were reported in parts of Arkansas, Delaware, Illinois, Indiana, Kansas, Kentucky, Maryland, Mississippi, Missouri, North Carolina, Oklahoma, Tennessee, and Virginia. The lone star tick is widely distributed with established populations in Alabama, Arkansas, Connecticut, Delaware, Florida, Georgia, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Michigan, Minnesota, Mississippi, Missouri, Nebraska, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, and West Virginia. 

While AGS is associated with tick bites, more research is needed to understand the role ticks play in starting this condition, and why certain people develop AGS. Anyone can develop AGS, but most cases have been reported in adults. 

Know how to recognize the symptoms of AGS and be prepared to test, diagnose, and manage AGS, particularly in states where lone star ticks are found. 

 

2. Tick bites are only one risk factor for developing AGS. 

Many people are bitten by lone star ticks and will never develop AGS. Scientists are exploring the connection between other risk factors and developing AGS. A recent study has shown that people diagnosed with AGS may be more likely to have a family member who was also diagnosed with AGS, have another food allergy, have an allergy to stinging or biting insects, or have A or O blood types.³ 

Research has also shown that environmental risk factors could contribute to developing AGS,⁴ like living in an area with lone star ticks, remembering finding a tick on themselves, recalling multiple tick bites, living near a wooded forest, spending more time outside, or living in areas with deer, such as larger properties, wooded forests, and properties with shrubs and brush. 

Ask your patient questions about other allergies and history of recent tick bites or outdoor exposure to help determine if testing for AGS is appropriate.

 

3. Symptoms of AGS are consistently inconsistent.

There is a spectrum of how sensitive AGS patients are to alpha-gal, and reactions are often different from person to person, which can make it difficult to diagnose. The first allergic reaction to AGS typically occurs between 1-6 months after a tick bite. Symptoms commonly appear 2-6 hours after being in contact with products containing alpha-gal, like red meat (beef, pork, lamb, venison, rabbit, or other meat from mammals), dairy, and some medications. Symptoms can range from mild to severe and include hives or itchy rash; swelling of the lips, throat, tongue, or eyelids; gastrointestinal symptoms such as nausea, vomiting, or diarrhea; heartburn or indigestion; cough, shortness of breath, or difficulty breathing; dizziness or a drop in blood pressure; or anaphylaxis.

Consider AGS if a patient reports waking up in the middle of the night with allergic symptoms after eating alpha-gal containing products for dinner, if allergic reactions are delayed, or if a patient has anaphylaxis of unknown cause, adult-onset allergy, or allergic symptoms and reports a recent tick bite. 

 

4. Diagnosing AGS requires a combination of a blood test and a physical exam.

Diagnosing AGS requires a detailed patient history, physical exam, and a blood test to detect specific immunoglobulin E (IgE) antibodies specific to alpha-gal (alpha-gal sIgE). Tests for alpha-gal sIgE antibodies are available at several large commercial laboratories and some academic institutions. Skin tests to identify reactions to allergens like pork or beef may also be used to inform AGS diagnosis. However, a positive alpha-gal sIgE test or skin test does not mean a person has AGS. Many people, particularly those who live in regions with lone star ticks, have positive alpha-gal specific IgE tests without having AGS. 

Consider the test results along with your patient’s symptoms and risk factors.

 

5. There is no treatment for AGS, but people can take prevention steps and AGS can be managed.

People can protect themselves and their family from AGS by preventing tick bites. Encourage your patients to use an Environmental Protection Agency–registered insect repellent outdoors, wear permethrin-treated clothing, and conduct thorough tick checks after outdoor activities. 

Once a person is no longer exposed to alpha-gal containing products, they should no longer experience symptoms. People with AGS should also proactively prevent tick bites. Tick bites can trigger or reactivate AGS.

For patients who have AGS, help manage their symptoms and identify alpha-gal containing products to avoid.

Dr. Kersh is Chief of the Rickettsial Zoonoses Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, and disclosed no relevant conflicts of interest.

CDC resources:

About Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Testing and Diagnosis for Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Resources | Alpha-gal Syndrome | CDC 

References 

Thompson JM et al. MMWR Morb Mortal Wkly Rep. 2023;72:815-820. 

Carpenter A et al. MMWR Morb Mortal Wkly Rep. 2023;72:809-814. Taylor ML et al. Ann Allergy, Asthma & Immunol. 2024 Jun;132(6):759.e2-764.e2. Kersh GJ et al. Ann Allergy, Asthma & Immunol. 2023 Apr;130(4):472-478.

Alpha-gal syndrome (AGS), a tickborne disease commonly called “red meat allergy,” is a serious, potentially life-threatening allergy to the carbohydrate alpha-gal. The alpha-gal carbohydrate is found in most mammals, though it is not in humans, apes, or old-world monkeys. People with AGS can have allergic reactions when they consume mammalian meat, dairy products, or other products derived from mammals. People often live with this disease for years before receiving a correct diagnosis, greatly impacting their quality of life. The number of suspected cases is also rising. 

More than 110,000 suspected AGS cases were identified between 2010 and 2022, according to a Centers for Disease Control and Prevention (CDC) report.¹ However, because the diagnosis requires a positive test and a clinical exam and some people may not get tested, as many as 450,000 people might be affected by AGS in the United States. Additionally, a CDC survey found that nearly half (42%) of US healthcare providers had never heard of AGS.² Among those who had, less than one third (29%) knew how to diagnose the condition. 

Here are 5 things clinicians need to know about AGS.

 

1. People can develop AGS after being bitten by a tick, primarily the lone star tick (Amblyomma americanum), in the United States.

In the United States, AGS is primarily associated with the bite of a lone star tick, but other kinds of ticks have not been ruled out. The majority of suspected AGS cases in the United States were reported in parts of Arkansas, Delaware, Illinois, Indiana, Kansas, Kentucky, Maryland, Mississippi, Missouri, North Carolina, Oklahoma, Tennessee, and Virginia. The lone star tick is widely distributed with established populations in Alabama, Arkansas, Connecticut, Delaware, Florida, Georgia, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Michigan, Minnesota, Mississippi, Missouri, Nebraska, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, and West Virginia. 

While AGS is associated with tick bites, more research is needed to understand the role ticks play in starting this condition, and why certain people develop AGS. Anyone can develop AGS, but most cases have been reported in adults. 

Know how to recognize the symptoms of AGS and be prepared to test, diagnose, and manage AGS, particularly in states where lone star ticks are found. 

 

2. Tick bites are only one risk factor for developing AGS. 

Many people are bitten by lone star ticks and will never develop AGS. Scientists are exploring the connection between other risk factors and developing AGS. A recent study has shown that people diagnosed with AGS may be more likely to have a family member who was also diagnosed with AGS, have another food allergy, have an allergy to stinging or biting insects, or have A or O blood types.³ 

Research has also shown that environmental risk factors could contribute to developing AGS,⁴ like living in an area with lone star ticks, remembering finding a tick on themselves, recalling multiple tick bites, living near a wooded forest, spending more time outside, or living in areas with deer, such as larger properties, wooded forests, and properties with shrubs and brush. 

Ask your patient questions about other allergies and history of recent tick bites or outdoor exposure to help determine if testing for AGS is appropriate.

 

3. Symptoms of AGS are consistently inconsistent.

There is a spectrum of how sensitive AGS patients are to alpha-gal, and reactions are often different from person to person, which can make it difficult to diagnose. The first allergic reaction to AGS typically occurs between 1-6 months after a tick bite. Symptoms commonly appear 2-6 hours after being in contact with products containing alpha-gal, like red meat (beef, pork, lamb, venison, rabbit, or other meat from mammals), dairy, and some medications. Symptoms can range from mild to severe and include hives or itchy rash; swelling of the lips, throat, tongue, or eyelids; gastrointestinal symptoms such as nausea, vomiting, or diarrhea; heartburn or indigestion; cough, shortness of breath, or difficulty breathing; dizziness or a drop in blood pressure; or anaphylaxis.

Consider AGS if a patient reports waking up in the middle of the night with allergic symptoms after eating alpha-gal containing products for dinner, if allergic reactions are delayed, or if a patient has anaphylaxis of unknown cause, adult-onset allergy, or allergic symptoms and reports a recent tick bite. 

 

4. Diagnosing AGS requires a combination of a blood test and a physical exam.

Diagnosing AGS requires a detailed patient history, physical exam, and a blood test to detect specific immunoglobulin E (IgE) antibodies specific to alpha-gal (alpha-gal sIgE). Tests for alpha-gal sIgE antibodies are available at several large commercial laboratories and some academic institutions. Skin tests to identify reactions to allergens like pork or beef may also be used to inform AGS diagnosis. However, a positive alpha-gal sIgE test or skin test does not mean a person has AGS. Many people, particularly those who live in regions with lone star ticks, have positive alpha-gal specific IgE tests without having AGS. 

Consider the test results along with your patient’s symptoms and risk factors.

 

5. There is no treatment for AGS, but people can take prevention steps and AGS can be managed.

People can protect themselves and their family from AGS by preventing tick bites. Encourage your patients to use an Environmental Protection Agency–registered insect repellent outdoors, wear permethrin-treated clothing, and conduct thorough tick checks after outdoor activities. 

Once a person is no longer exposed to alpha-gal containing products, they should no longer experience symptoms. People with AGS should also proactively prevent tick bites. Tick bites can trigger or reactivate AGS.

For patients who have AGS, help manage their symptoms and identify alpha-gal containing products to avoid.

Dr. Kersh is Chief of the Rickettsial Zoonoses Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, and disclosed no relevant conflicts of interest.

CDC resources:

About Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Testing and Diagnosis for Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Resources | Alpha-gal Syndrome | CDC 

References 

Thompson JM et al. MMWR Morb Mortal Wkly Rep. 2023;72:815-820. 

Carpenter A et al. MMWR Morb Mortal Wkly Rep. 2023;72:809-814. Taylor ML et al. Ann Allergy, Asthma & Immunol. 2024 Jun;132(6):759.e2-764.e2. Kersh GJ et al. Ann Allergy, Asthma & Immunol. 2023 Apr;130(4):472-478.

NEW YORK, NY — Work over the past several years has reframed hidradenitis suppurativa (HS) as a large-field inflammatory process, a recharacterization that has immediate relevance to treatment strategies and goals, according to two investigators intimately involved in much of the recent progress.

“Success is being achieved by targeting multiple inflammatory axes in HS, and therapeutics are evolving rapidly,” reported James G. Krueger, MD, PhD, head of the Laboratory of Investigative Dermatology, Rockefeller University, New York, NY.

The activity of targeted anti-inflammatory therapies — bimekizumab just joined adalimumab and secukinumab as a third approved biologic for HS — is not news, but the degree to which inflammation is upregulated systemically, not just at areas of skin involvement, has changed the conceptualization of HS.

HS Is a Systemic Inflammatory Disease

Relative to psoriasis, for which there are many parallels, “HS is hugely more inflammatory in the systemic circulation,” Krueger said at the 27th Annual Winter Symposium — Advances in Medical and Surgical Dermatology (MSWS) 2024. Yet, HS is also more complex involving additional pathways that appear to include dysbiosis. The concept of follicular occlusion, once a common explanation for HS, has been left far behind.

“Unlike psoriasis, which we can treat really well by inhibiting a single pathway target, HS is just not that simple,” Krueger said. Although largely an inflammatory process, the cascade of inflammatory factors for specific manifestations, such as tunnels, means that optimal therapy in one case might have little benefit in another.

The relatively new evidence that HS activity is not confined to lesional skin might be the most important recent step toward new strategies to target disease. These studies were performed by Kristina Navrazhina, MD, PhD, now a resident in dermatology at the Icahn School of Medicine at Mount Sinai, New York. She received her PhD while studying HS activity in non-lesional skin. Her work has led her to conclude that the best chance for better outcomes in HS is early diagnosis and treatment. Although this is generally true of any pathology, the changes in the HS phenotype once fistulae form includes a poor response to conventional therapies. 

In fact, based on her work in evaluating HS activity in non-lesional skin, Navrazhina has shown that “many patients with modest lesions already have advanced disease.” Consistent with the premise that HS is a deeply systemic inflammatory process, nodules, considered an early manifestation, turn out to be “the tip of the iceberg.”

 

Non-Lesional HS Skin Is Inflamed

When she has employed RNA sequencing based on tape strip sampling from completely normal skin away from nodules, interleukin (IL)-17 and a broad array of other inflammatory markers were found to be upregulated. When she performed ultrasound to look for disease activity under the normal skin, she has often found tunnels already formed. Doppler ultrasound showed some of these tunnels were actively draining.

This might provide a partial explanation for why therapies are not always effective even when clinical signs of disease are modest. 

“Are we missing the opportunity for intervening?” Navrazhina asked, noting that early intervention has been limited traditionally by extremely long diagnostic delays. Citing the literature, Navrazhina said the average delay is 7 years for HS versus 1 year for psoriasis. Patients often cycle through 3 or 4 providers before the diagnosis is made, she said.

Awakening first-line clinicians to the signs and symptoms of HS, whether in the emergency room or primary care, is a critical message because of the incrementally difficult task to control disease once fistulae have formed. 

Krueger made the same appeal. For the neutrophilic inflammation that characterizes nodules, targeted therapies are often effective, but he agreed that available therapies are generally far less so once tunnels form.

 

Role Seen for Bacteria in HS Pathogenesis

One reason might be an interaction between anaerobic bacteria and the keratinocytes that form the tunnel walls, according to Krueger. Although HS is not typically considered an infectious disease, he reported that the interaction of these bacteria with keratinocytes is associated with expression of approximately 1000 inflammatory gene products. The process of tunnel formation is traced to how factors recruited by upregulated inflammation, such as chemokines, coordinate.

He described recent work pursing novel strategies such as highly targeted antibiotics or inhibitors of complement factor C5a, which has been proposed as a biomarker for HS, to intervene in preventing or reversing HS tunnels. 

While this work progresses, one of the most Important unmet needs in HS is an accepted measure of clinically meaningful improvement in advanced disease, particularly the impact of therapy on HS tunnels, according to Krueger. 

“There is no measure of tunnel activity that the FDA accepts in evaluating drugs,” he noted, which will be essential for approving therapies that offer this benefit. 

A phase 3 trials program for one of the promising drugs, sonelokimab, was announced early in 2024. A nanobody that targets IL-17A/A, IL-17A/F, and IL-17F/F, the small size of this molecule permits exceptional tissue penetration while the broad anti-IL-17 activity has a high degree of theoretical potential in late-stage HS, according to Krueger. 

There are numerous pieces of the HS puzzle that are still missing, but both Krueger and Navrazhina are enthusiastic about new targets and opportunities for disease control that are stemming from a better understanding of the underlying pathophysiology. Not least, both indicated that testing for inflammatory phenotypes will allow for individualized therapeutic choices with a maximum likelihood of response, particularly if earlier diagnosis permits earlier treatment. 

“Due to the heterogeneity of HS, it is hard to know who will respond to which treatment or which treatment should be started first,” Navrazhina said. She thinks that early measures of the inflammatory profile in nodules or even non-lesional skin might provide that guidance. 

Both Krueger and Navrazhina reported no financial relationships relevant to this work. 

 

A version of this article appeared on Medscape.com.

NEW YORK, NY — Work over the past several years has reframed hidradenitis suppurativa (HS) as a large-field inflammatory process, a recharacterization that has immediate relevance to treatment strategies and goals, according to two investigators intimately involved in much of the recent progress.

“Success is being achieved by targeting multiple inflammatory axes in HS, and therapeutics are evolving rapidly,” reported James G. Krueger, MD, PhD, head of the Laboratory of Investigative Dermatology, Rockefeller University, New York, NY.

The activity of targeted anti-inflammatory therapies — bimekizumab just joined adalimumab and secukinumab as a third approved biologic for HS — is not news, but the degree to which inflammation is upregulated systemically, not just at areas of skin involvement, has changed the conceptualization of HS.

HS Is a Systemic Inflammatory Disease

Relative to psoriasis, for which there are many parallels, “HS is hugely more inflammatory in the systemic circulation,” Krueger said at the 27th Annual Winter Symposium — Advances in Medical and Surgical Dermatology (MSWS) 2024. Yet, HS is also more complex involving additional pathways that appear to include dysbiosis. The concept of follicular occlusion, once a common explanation for HS, has been left far behind.

“Unlike psoriasis, which we can treat really well by inhibiting a single pathway target, HS is just not that simple,” Krueger said. Although largely an inflammatory process, the cascade of inflammatory factors for specific manifestations, such as tunnels, means that optimal therapy in one case might have little benefit in another.

The relatively new evidence that HS activity is not confined to lesional skin might be the most important recent step toward new strategies to target disease. These studies were performed by Kristina Navrazhina, MD, PhD, now a resident in dermatology at the Icahn School of Medicine at Mount Sinai, New York. She received her PhD while studying HS activity in non-lesional skin. Her work has led her to conclude that the best chance for better outcomes in HS is early diagnosis and treatment. Although this is generally true of any pathology, the changes in the HS phenotype once fistulae form includes a poor response to conventional therapies. 

In fact, based on her work in evaluating HS activity in non-lesional skin, Navrazhina has shown that “many patients with modest lesions already have advanced disease.” Consistent with the premise that HS is a deeply systemic inflammatory process, nodules, considered an early manifestation, turn out to be “the tip of the iceberg.”

 

Non-Lesional HS Skin Is Inflamed

When she has employed RNA sequencing based on tape strip sampling from completely normal skin away from nodules, interleukin (IL)-17 and a broad array of other inflammatory markers were found to be upregulated. When she performed ultrasound to look for disease activity under the normal skin, she has often found tunnels already formed. Doppler ultrasound showed some of these tunnels were actively draining.

This might provide a partial explanation for why therapies are not always effective even when clinical signs of disease are modest. 

“Are we missing the opportunity for intervening?” Navrazhina asked, noting that early intervention has been limited traditionally by extremely long diagnostic delays. Citing the literature, Navrazhina said the average delay is 7 years for HS versus 1 year for psoriasis. Patients often cycle through 3 or 4 providers before the diagnosis is made, she said.

Awakening first-line clinicians to the signs and symptoms of HS, whether in the emergency room or primary care, is a critical message because of the incrementally difficult task to control disease once fistulae have formed. 

Krueger made the same appeal. For the neutrophilic inflammation that characterizes nodules, targeted therapies are often effective, but he agreed that available therapies are generally far less so once tunnels form.

 

Role Seen for Bacteria in HS Pathogenesis

One reason might be an interaction between anaerobic bacteria and the keratinocytes that form the tunnel walls, according to Krueger. Although HS is not typically considered an infectious disease, he reported that the interaction of these bacteria with keratinocytes is associated with expression of approximately 1000 inflammatory gene products. The process of tunnel formation is traced to how factors recruited by upregulated inflammation, such as chemokines, coordinate.

He described recent work pursing novel strategies such as highly targeted antibiotics or inhibitors of complement factor C5a, which has been proposed as a biomarker for HS, to intervene in preventing or reversing HS tunnels. 

While this work progresses, one of the most Important unmet needs in HS is an accepted measure of clinically meaningful improvement in advanced disease, particularly the impact of therapy on HS tunnels, according to Krueger. 

“There is no measure of tunnel activity that the FDA accepts in evaluating drugs,” he noted, which will be essential for approving therapies that offer this benefit. 

A phase 3 trials program for one of the promising drugs, sonelokimab, was announced early in 2024. A nanobody that targets IL-17A/A, IL-17A/F, and IL-17F/F, the small size of this molecule permits exceptional tissue penetration while the broad anti-IL-17 activity has a high degree of theoretical potential in late-stage HS, according to Krueger. 

There are numerous pieces of the HS puzzle that are still missing, but both Krueger and Navrazhina are enthusiastic about new targets and opportunities for disease control that are stemming from a better understanding of the underlying pathophysiology. Not least, both indicated that testing for inflammatory phenotypes will allow for individualized therapeutic choices with a maximum likelihood of response, particularly if earlier diagnosis permits earlier treatment. 

“Due to the heterogeneity of HS, it is hard to know who will respond to which treatment or which treatment should be started first,” Navrazhina said. She thinks that early measures of the inflammatory profile in nodules or even non-lesional skin might provide that guidance. 

Both Krueger and Navrazhina reported no financial relationships relevant to this work. 

 

A version of this article appeared on Medscape.com.

NEW YORK, NY — Work over the past several years has reframed hidradenitis suppurativa (HS) as a large-field inflammatory process, a recharacterization that has immediate relevance to treatment strategies and goals, according to two investigators intimately involved in much of the recent progress.

“Success is being achieved by targeting multiple inflammatory axes in HS, and therapeutics are evolving rapidly,” reported James G. Krueger, MD, PhD, head of the Laboratory of Investigative Dermatology, Rockefeller University, New York, NY.

The activity of targeted anti-inflammatory therapies — bimekizumab just joined adalimumab and secukinumab as a third approved biologic for HS — is not news, but the degree to which inflammation is upregulated systemically, not just at areas of skin involvement, has changed the conceptualization of HS.

HS Is a Systemic Inflammatory Disease

Relative to psoriasis, for which there are many parallels, “HS is hugely more inflammatory in the systemic circulation,” Krueger said at the 27th Annual Winter Symposium — Advances in Medical and Surgical Dermatology (MSWS) 2024. Yet, HS is also more complex involving additional pathways that appear to include dysbiosis. The concept of follicular occlusion, once a common explanation for HS, has been left far behind.

“Unlike psoriasis, which we can treat really well by inhibiting a single pathway target, HS is just not that simple,” Krueger said. Although largely an inflammatory process, the cascade of inflammatory factors for specific manifestations, such as tunnels, means that optimal therapy in one case might have little benefit in another.

The relatively new evidence that HS activity is not confined to lesional skin might be the most important recent step toward new strategies to target disease. These studies were performed by Kristina Navrazhina, MD, PhD, now a resident in dermatology at the Icahn School of Medicine at Mount Sinai, New York. She received her PhD while studying HS activity in non-lesional skin. Her work has led her to conclude that the best chance for better outcomes in HS is early diagnosis and treatment. Although this is generally true of any pathology, the changes in the HS phenotype once fistulae form includes a poor response to conventional therapies. 

In fact, based on her work in evaluating HS activity in non-lesional skin, Navrazhina has shown that “many patients with modest lesions already have advanced disease.” Consistent with the premise that HS is a deeply systemic inflammatory process, nodules, considered an early manifestation, turn out to be “the tip of the iceberg.”

 

Non-Lesional HS Skin Is Inflamed

When she has employed RNA sequencing based on tape strip sampling from completely normal skin away from nodules, interleukin (IL)-17 and a broad array of other inflammatory markers were found to be upregulated. When she performed ultrasound to look for disease activity under the normal skin, she has often found tunnels already formed. Doppler ultrasound showed some of these tunnels were actively draining.

This might provide a partial explanation for why therapies are not always effective even when clinical signs of disease are modest. 

“Are we missing the opportunity for intervening?” Navrazhina asked, noting that early intervention has been limited traditionally by extremely long diagnostic delays. Citing the literature, Navrazhina said the average delay is 7 years for HS versus 1 year for psoriasis. Patients often cycle through 3 or 4 providers before the diagnosis is made, she said.

Awakening first-line clinicians to the signs and symptoms of HS, whether in the emergency room or primary care, is a critical message because of the incrementally difficult task to control disease once fistulae have formed. 

Krueger made the same appeal. For the neutrophilic inflammation that characterizes nodules, targeted therapies are often effective, but he agreed that available therapies are generally far less so once tunnels form.

 

Role Seen for Bacteria in HS Pathogenesis

One reason might be an interaction between anaerobic bacteria and the keratinocytes that form the tunnel walls, according to Krueger. Although HS is not typically considered an infectious disease, he reported that the interaction of these bacteria with keratinocytes is associated with expression of approximately 1000 inflammatory gene products. The process of tunnel formation is traced to how factors recruited by upregulated inflammation, such as chemokines, coordinate.

He described recent work pursing novel strategies such as highly targeted antibiotics or inhibitors of complement factor C5a, which has been proposed as a biomarker for HS, to intervene in preventing or reversing HS tunnels. 

While this work progresses, one of the most Important unmet needs in HS is an accepted measure of clinically meaningful improvement in advanced disease, particularly the impact of therapy on HS tunnels, according to Krueger. 

“There is no measure of tunnel activity that the FDA accepts in evaluating drugs,” he noted, which will be essential for approving therapies that offer this benefit. 

A phase 3 trials program for one of the promising drugs, sonelokimab, was announced early in 2024. A nanobody that targets IL-17A/A, IL-17A/F, and IL-17F/F, the small size of this molecule permits exceptional tissue penetration while the broad anti-IL-17 activity has a high degree of theoretical potential in late-stage HS, according to Krueger. 

There are numerous pieces of the HS puzzle that are still missing, but both Krueger and Navrazhina are enthusiastic about new targets and opportunities for disease control that are stemming from a better understanding of the underlying pathophysiology. Not least, both indicated that testing for inflammatory phenotypes will allow for individualized therapeutic choices with a maximum likelihood of response, particularly if earlier diagnosis permits earlier treatment. 

“Due to the heterogeneity of HS, it is hard to know who will respond to which treatment or which treatment should be started first,” Navrazhina said. She thinks that early measures of the inflammatory profile in nodules or even non-lesional skin might provide that guidance. 

Both Krueger and Navrazhina reported no financial relationships relevant to this work. 

 

A version of this article appeared on Medscape.com.