Photo Challenge

The Diagnosis: Cutaneous Amyloidosis

A punch biopsy confirmed the diagnosis of cutaneous amyloidosis, which is characterized by the deposition of amyloid proteins in the skin without systemic involvement. Subtypes of cutaneous amyloidosis include lichenoid, macular, and nodular amyloidosis. A mixed or biphasic amyloidosis can occur when both lichenoid and macular lesions are present.¹ Lichenoid and macular amyloidosis generally are characterized by moderate to severe pruritus. Lichenoid amyloidosis favors the shins, calves, ankles, and extensor extremities; macular amyloidosis has a predilection for the interscapular area and less frequently the upper arms, chest, and thighs.² Atypical variants also have been reported, including amyloidosis cutis dyschromica, poikilodermalike amyloidosis, and bullous amyloidosis, as well as incontinentia pigmenti–like, linear, and nevoid types.³ Macular amyloidosis has been reported to occur in association with progressive systemic sclerosis, primary biliary cirrhosis, systemic lupus erythematosus, paronychia, and multiple endocrine neoplasia type 2.²

Acanthosis nigricans typically presents on the neck and intertriginous areas as velvety hyperpigmented plaques. Confluent and reticulated papillomatosis also appears as slightly elevated papules; however, it occurs in the intermammary region in a reticulated pattern. Ichthyosis vulgaris also may occur on the lower extremities but presents with adherent large scales rather than papules. Keratosis pilaris may present on the proximal lower extremities with smaller, folliculocentric, fleshcolored to pink papules.

Treatment of cutaneous amyloidosis has long been challenging for dermatologists. The primary focus should be treatment of any underlying disease that is causing the pruritus and subsequent manipulation of skin lesions. Topical calcipotriol, phototherapy, oral cyclophosphamide, and Nd:YAG laser have demonstrated beneficial outcomes. IL-31 antibodies may be a potential future treatment.¹

The Diagnosis: Cutaneous Amyloidosis

A punch biopsy confirmed the diagnosis of cutaneous amyloidosis, which is characterized by the deposition of amyloid proteins in the skin without systemic involvement. Subtypes of cutaneous amyloidosis include lichenoid, macular, and nodular amyloidosis. A mixed or biphasic amyloidosis can occur when both lichenoid and macular lesions are present.¹ Lichenoid and macular amyloidosis generally are characterized by moderate to severe pruritus. Lichenoid amyloidosis favors the shins, calves, ankles, and extensor extremities; macular amyloidosis has a predilection for the interscapular area and less frequently the upper arms, chest, and thighs.² Atypical variants also have been reported, including amyloidosis cutis dyschromica, poikilodermalike amyloidosis, and bullous amyloidosis, as well as incontinentia pigmenti–like, linear, and nevoid types.³ Macular amyloidosis has been reported to occur in association with progressive systemic sclerosis, primary biliary cirrhosis, systemic lupus erythematosus, paronychia, and multiple endocrine neoplasia type 2.²

Acanthosis nigricans typically presents on the neck and intertriginous areas as velvety hyperpigmented plaques. Confluent and reticulated papillomatosis also appears as slightly elevated papules; however, it occurs in the intermammary region in a reticulated pattern. Ichthyosis vulgaris also may occur on the lower extremities but presents with adherent large scales rather than papules. Keratosis pilaris may present on the proximal lower extremities with smaller, folliculocentric, fleshcolored to pink papules.

Treatment of cutaneous amyloidosis has long been challenging for dermatologists. The primary focus should be treatment of any underlying disease that is causing the pruritus and subsequent manipulation of skin lesions. Topical calcipotriol, phototherapy, oral cyclophosphamide, and Nd:YAG laser have demonstrated beneficial outcomes. IL-31 antibodies may be a potential future treatment.¹

The Diagnosis: Cutaneous Amyloidosis

A punch biopsy confirmed the diagnosis of cutaneous amyloidosis, which is characterized by the deposition of amyloid proteins in the skin without systemic involvement. Subtypes of cutaneous amyloidosis include lichenoid, macular, and nodular amyloidosis. A mixed or biphasic amyloidosis can occur when both lichenoid and macular lesions are present.¹ Lichenoid and macular amyloidosis generally are characterized by moderate to severe pruritus. Lichenoid amyloidosis favors the shins, calves, ankles, and extensor extremities; macular amyloidosis has a predilection for the interscapular area and less frequently the upper arms, chest, and thighs.² Atypical variants also have been reported, including amyloidosis cutis dyschromica, poikilodermalike amyloidosis, and bullous amyloidosis, as well as incontinentia pigmenti–like, linear, and nevoid types.³ Macular amyloidosis has been reported to occur in association with progressive systemic sclerosis, primary biliary cirrhosis, systemic lupus erythematosus, paronychia, and multiple endocrine neoplasia type 2.²

Acanthosis nigricans typically presents on the neck and intertriginous areas as velvety hyperpigmented plaques. Confluent and reticulated papillomatosis also appears as slightly elevated papules; however, it occurs in the intermammary region in a reticulated pattern. Ichthyosis vulgaris also may occur on the lower extremities but presents with adherent large scales rather than papules. Keratosis pilaris may present on the proximal lower extremities with smaller, folliculocentric, fleshcolored to pink papules.

Treatment of cutaneous amyloidosis has long been challenging for dermatologists. The primary focus should be treatment of any underlying disease that is causing the pruritus and subsequent manipulation of skin lesions. Topical calcipotriol, phototherapy, oral cyclophosphamide, and Nd:YAG laser have demonstrated beneficial outcomes. IL-31 antibodies may be a potential future treatment.¹

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

The Diagnosis: Lupus Erythematosus Tumidus

Histopathologic evaluation of a punch biopsy revealed focal dermal mucin deposition and CD123+ discrete clusters of plasmacytoid dendritic cells without interface changes (Figure 1), favoring a diagnosis of lupus erythematosus tumidus (LET) in our patient. There was no clinical improvement in symptoms when she previously was treated with topical antifungals or class III corticosteroid creams. Tacrolimus ointment 0.1% twice daily for 1 month did not result in substantial improvement in the appearance of the plaque, and it spontaneously resolved after 2 to 3 months. She declined treatment with hydroxychloroquine.

Lupus erythematosus tumidus is an uncommon subtype of chronic cutaneous lupus erythematosus with no distinct etiology. It is clinically characterized by edematous, urticarial, single or multiple plaques with a smooth surface affecting sun-exposed areas that can last for months to years.¹ In contrast to other variations of chronic cutaneous lupus such as discoid lupus erythematosus, LET lesions lack surface papulosquamous features such as scaling, atrophy, and follicular plugging.^1-4 Based solely on histologic findings, LET may be indistinguishable from reticular erythematous mucinosis and Jessner lymphocytic infiltration of the skin (JLIS) due to a similar lack of epidermal involvement and presence of a perivascular lymphocytic infiltrate (Figure 2).

The average age at disease onset is 36 years, nearly the same as that described in discoid lupus erythematosus.⁴ Lupus erythematosus tumidus has a favorable prognosis and commonly presents without other autoimmune signs, serologic abnormalities, or gender preference, with concomitant systemic lupus erythematosus sometimes reported.⁵

The absence of clinical and histological epidermal involvement are the most important clues to aid in the diagnosis. It has been postulated that JLIS could be an early cutaneous manifestation of LET.⁶ The differential diagnosis also may include erythema annulare centrifugum, granuloma annulare, and urticarial vasculitis. Lesions typically respond well to photoprotection, topical corticosteroids, and/or antimalarials. The addition of tacrolimus ointment 0.1% may result in complete regression without recurrence.⁷

Erythema annulare centrifugum is a reactive erythema that classically begins as a pink papule that gradually enlarges to form an annular erythematous plaque with a fine trailing scale that may recur.⁸ The histopathology of erythema annulare centrifugum shares features seen in LET, making the diagnosis difficult; however, secondary changes to the epidermis (eg, spongiosis, hyperkeratosis) may be seen. This condition has been associated with lymphoproliferative malignancies.⁸

Reticular erythematous mucinosis is clinically distinguished from LET, as it presents as reticular, rather than arciform, erythematous macules, papules, or plaques that may be asymptomatic or pruritic.⁹ Histopathology typically shows more superficial mucin deposition than in LET as well as superficial to mid-dermal perivascular and periadnexal lymphocytic infiltrates. Reticular erythematous mucinosis more frequently is reported in women in their 30s and 40s and has been associated with UV exposure and hormonal triggers, such as oral contraceptive medications and pregnancy.⁹

Granuloma annulare typically presents as asymptomatic, erythematous, annular plaques or papules in young women.¹⁰ There are several histologic subtypes that show focal collagen degeneration, inflammation with palisaded or interstitial histiocytes, and mucin deposition, regardless of clinical presentation. Granuloma annulare has been associated with systemic diseases including type 2 diabetes mellitus and thyroid disease. Localized granuloma annulare most commonly presents on the dorsal aspects of the hands or feet.¹⁰

We present a case of LET on the face. Although histologically similar to other dermatoses, LET often lacks epidermal involvement and presents on sun-exposed areas of the body. Jessner lymphocytic infiltration of the skin also should be considered in the differential, as there is an overlap of clinical and histopathological features; JLIS lacks mucin deposits.⁶ This case reinforces the importance of correlating clinical with histopathologic findings. Our patient was treated with tacrolimus ointment 0.1%, and the plaque eventually resolved in 2 to 3 months without recurrence. This condition should be included in the differential diagnosis of recurring annular plaques on sunexposed areas, particularly in middle-aged adults, even in the absence of systemic involvement.

The Diagnosis: Lupus Erythematosus Tumidus

Histopathologic evaluation of a punch biopsy revealed focal dermal mucin deposition and CD123+ discrete clusters of plasmacytoid dendritic cells without interface changes (Figure 1), favoring a diagnosis of lupus erythematosus tumidus (LET) in our patient. There was no clinical improvement in symptoms when she previously was treated with topical antifungals or class III corticosteroid creams. Tacrolimus ointment 0.1% twice daily for 1 month did not result in substantial improvement in the appearance of the plaque, and it spontaneously resolved after 2 to 3 months. She declined treatment with hydroxychloroquine.

Lupus erythematosus tumidus is an uncommon subtype of chronic cutaneous lupus erythematosus with no distinct etiology. It is clinically characterized by edematous, urticarial, single or multiple plaques with a smooth surface affecting sun-exposed areas that can last for months to years.¹ In contrast to other variations of chronic cutaneous lupus such as discoid lupus erythematosus, LET lesions lack surface papulosquamous features such as scaling, atrophy, and follicular plugging.^1-4 Based solely on histologic findings, LET may be indistinguishable from reticular erythematous mucinosis and Jessner lymphocytic infiltration of the skin (JLIS) due to a similar lack of epidermal involvement and presence of a perivascular lymphocytic infiltrate (Figure 2).

The average age at disease onset is 36 years, nearly the same as that described in discoid lupus erythematosus.⁴ Lupus erythematosus tumidus has a favorable prognosis and commonly presents without other autoimmune signs, serologic abnormalities, or gender preference, with concomitant systemic lupus erythematosus sometimes reported.⁵

The absence of clinical and histological epidermal involvement are the most important clues to aid in the diagnosis. It has been postulated that JLIS could be an early cutaneous manifestation of LET.⁶ The differential diagnosis also may include erythema annulare centrifugum, granuloma annulare, and urticarial vasculitis. Lesions typically respond well to photoprotection, topical corticosteroids, and/or antimalarials. The addition of tacrolimus ointment 0.1% may result in complete regression without recurrence.⁷

Erythema annulare centrifugum is a reactive erythema that classically begins as a pink papule that gradually enlarges to form an annular erythematous plaque with a fine trailing scale that may recur.⁸ The histopathology of erythema annulare centrifugum shares features seen in LET, making the diagnosis difficult; however, secondary changes to the epidermis (eg, spongiosis, hyperkeratosis) may be seen. This condition has been associated with lymphoproliferative malignancies.⁸

Reticular erythematous mucinosis is clinically distinguished from LET, as it presents as reticular, rather than arciform, erythematous macules, papules, or plaques that may be asymptomatic or pruritic.⁹ Histopathology typically shows more superficial mucin deposition than in LET as well as superficial to mid-dermal perivascular and periadnexal lymphocytic infiltrates. Reticular erythematous mucinosis more frequently is reported in women in their 30s and 40s and has been associated with UV exposure and hormonal triggers, such as oral contraceptive medications and pregnancy.⁹

Granuloma annulare typically presents as asymptomatic, erythematous, annular plaques or papules in young women.¹⁰ There are several histologic subtypes that show focal collagen degeneration, inflammation with palisaded or interstitial histiocytes, and mucin deposition, regardless of clinical presentation. Granuloma annulare has been associated with systemic diseases including type 2 diabetes mellitus and thyroid disease. Localized granuloma annulare most commonly presents on the dorsal aspects of the hands or feet.¹⁰

We present a case of LET on the face. Although histologically similar to other dermatoses, LET often lacks epidermal involvement and presents on sun-exposed areas of the body. Jessner lymphocytic infiltration of the skin also should be considered in the differential, as there is an overlap of clinical and histopathological features; JLIS lacks mucin deposits.⁶ This case reinforces the importance of correlating clinical with histopathologic findings. Our patient was treated with tacrolimus ointment 0.1%, and the plaque eventually resolved in 2 to 3 months without recurrence. This condition should be included in the differential diagnosis of recurring annular plaques on sunexposed areas, particularly in middle-aged adults, even in the absence of systemic involvement.

The Diagnosis: Lupus Erythematosus Tumidus

Histopathologic evaluation of a punch biopsy revealed focal dermal mucin deposition and CD123+ discrete clusters of plasmacytoid dendritic cells without interface changes (Figure 1), favoring a diagnosis of lupus erythematosus tumidus (LET) in our patient. There was no clinical improvement in symptoms when she previously was treated with topical antifungals or class III corticosteroid creams. Tacrolimus ointment 0.1% twice daily for 1 month did not result in substantial improvement in the appearance of the plaque, and it spontaneously resolved after 2 to 3 months. She declined treatment with hydroxychloroquine.

Lupus erythematosus tumidus is an uncommon subtype of chronic cutaneous lupus erythematosus with no distinct etiology. It is clinically characterized by edematous, urticarial, single or multiple plaques with a smooth surface affecting sun-exposed areas that can last for months to years.¹ In contrast to other variations of chronic cutaneous lupus such as discoid lupus erythematosus, LET lesions lack surface papulosquamous features such as scaling, atrophy, and follicular plugging.^1-4 Based solely on histologic findings, LET may be indistinguishable from reticular erythematous mucinosis and Jessner lymphocytic infiltration of the skin (JLIS) due to a similar lack of epidermal involvement and presence of a perivascular lymphocytic infiltrate (Figure 2).

The average age at disease onset is 36 years, nearly the same as that described in discoid lupus erythematosus.⁴ Lupus erythematosus tumidus has a favorable prognosis and commonly presents without other autoimmune signs, serologic abnormalities, or gender preference, with concomitant systemic lupus erythematosus sometimes reported.⁵

The absence of clinical and histological epidermal involvement are the most important clues to aid in the diagnosis. It has been postulated that JLIS could be an early cutaneous manifestation of LET.⁶ The differential diagnosis also may include erythema annulare centrifugum, granuloma annulare, and urticarial vasculitis. Lesions typically respond well to photoprotection, topical corticosteroids, and/or antimalarials. The addition of tacrolimus ointment 0.1% may result in complete regression without recurrence.⁷

Erythema annulare centrifugum is a reactive erythema that classically begins as a pink papule that gradually enlarges to form an annular erythematous plaque with a fine trailing scale that may recur.⁸ The histopathology of erythema annulare centrifugum shares features seen in LET, making the diagnosis difficult; however, secondary changes to the epidermis (eg, spongiosis, hyperkeratosis) may be seen. This condition has been associated with lymphoproliferative malignancies.⁸

Reticular erythematous mucinosis is clinically distinguished from LET, as it presents as reticular, rather than arciform, erythematous macules, papules, or plaques that may be asymptomatic or pruritic.⁹ Histopathology typically shows more superficial mucin deposition than in LET as well as superficial to mid-dermal perivascular and periadnexal lymphocytic infiltrates. Reticular erythematous mucinosis more frequently is reported in women in their 30s and 40s and has been associated with UV exposure and hormonal triggers, such as oral contraceptive medications and pregnancy.⁹

Granuloma annulare typically presents as asymptomatic, erythematous, annular plaques or papules in young women.¹⁰ There are several histologic subtypes that show focal collagen degeneration, inflammation with palisaded or interstitial histiocytes, and mucin deposition, regardless of clinical presentation. Granuloma annulare has been associated with systemic diseases including type 2 diabetes mellitus and thyroid disease. Localized granuloma annulare most commonly presents on the dorsal aspects of the hands or feet.¹⁰

We present a case of LET on the face. Although histologically similar to other dermatoses, LET often lacks epidermal involvement and presents on sun-exposed areas of the body. Jessner lymphocytic infiltration of the skin also should be considered in the differential, as there is an overlap of clinical and histopathological features; JLIS lacks mucin deposits.⁶ This case reinforces the importance of correlating clinical with histopathologic findings. Our patient was treated with tacrolimus ointment 0.1%, and the plaque eventually resolved in 2 to 3 months without recurrence. This condition should be included in the differential diagnosis of recurring annular plaques on sunexposed areas, particularly in middle-aged adults, even in the absence of systemic involvement.

The Diagnosis: Calciphylaxis

Histopathology revealed epidermal and dermal necrosis, a perivascular neutrophilic infiltrate, and scattered microcalcifications within small- and medium-sized subcutaneous vessels, consistent with a diagnosis of calciphylaxis (Figure). Calciphylaxis (also known as calcific uremic arteriolopathy) is a rare, severe, and often fatal vasculopathy that predominately occurs in patients with end-stage renal failure.¹ The pathogenesis of calciphylaxis remains poorly understood; however, it generally is thought that an imbalance in calcium homeostasis in susceptible hosts results in the precipitation of calcium phosphate within vessel walls leading to endothelial damage with subsequent thrombotic vasculopathy and ischemic tissue damage. Acquired and congenital hypercoagulable states have been implicated in the pathogenesis of calciphylaxis.²

Treatment of calciphylaxis is directed at normalizing abnormal calcium metabolism; removing possible exacerbating agents, such as warfarin, systemic corticosteroids, calcium, and iron; and transitioning patients with end-stage renal disease to hemodialysis, if not already initiated. The treatment approach is multifaceted, and numerous therapies usually are attempted simultaneously. Vitamin K supplementation, low-calcium dialysate, non–calcium carbonate phosphate binders, cinacalcet, becaplermin, bisphosphonates, hyperbaric oxygen, and intravenous sodium thiosulfate all have been utilized with some success. Currently, intravenous sodium thiosulfate is the mainstay therapy for the treatment of calciphylaxis.² Although the mechanism of sodium thiosulfate is not entirely understood, it is known to have anticalcification, vasodilatory, and antioxidant properties.

Retiform purpura clinically is characterized by reticulated, branching, purpuric skin lesions. It occurs following vascular insult by way of vessel lumen occlusion (thrombotic vasculopathy) and less frequently by vessel wall inflammation (vasculitis). The differential diagnosis for retiform purpura includes various causes of microvascular occlusion, including hypercoagulable states and type I cryoglobulinemia, calciphylaxis, infections, autoimmune vasculitic conditions, and embolic causes.³

Cutaneous disease in individuals with antiphospholipid antibodies may present similarly with retiform purpura in the form of necrotizing livedo reticularis, leg ulcers, or widespread cutaneous necrosis. Histopathologic findings include vascular thrombi with partial or complete obstruction of the small- to medium-sized arteries at the dermoepidermal junction, often in the absence of an inflammatory infiltrate.⁴ True vasculitis is not typical of antiphospholipid syndrome.

Medium vessel vasculitides, such as polyarteritis nodosa, clinically present with livedo reticularis, subcutaneous nodules, and tissue necrosis. Dermatopathologic evaluation of a medium-sized vessel vasculitis would demonstrate a neutrophilic vasculitis involving vessels within the deep dermis and septa of subcutaneous fat.⁵ Tissue sampling should be deep and wide enough to visualize the pathology, as shallow biopsies may show intraluminal thrombi of the superficial dermal plexus only, while a narrow specimen may result in falsenegative findings due to the focal nature of vessel involvement in conditions such as polyarteritis nodosa.

Type I cryoglobulinemia often is a manifestation of plasma cell dyscrasia and commonly presents with Raynaud phenomenon, livedo reticularis, and acrocyanosis of helices⁶ ; pathology demonstrates vessel occlusion and erythrocyte extravasation. In contrast, types II and III, also known as mixed cryoglobulinemia, are associated with hepatitis C and autoimmune connective tissue disease. They clinically present as purpuric plaques and nodules that have a propensity to vesiculate and ulcerate.⁷ Histopathologically, features of leukocytoclastic vasculitis are seen, and direct immunofluorescence demonstrates perivascular granular deposits consisting predominantly of IgM and C3 in the papillary dermis.⁸

Warfarin therapy, particularly in high initial doses, can induce lesions of cutaneous necrosis, which clinically may resemble the appearance of calciphylaxis. Warfarininduced skin necrosis typically occurs 3 to 5 days after the initiation of therapy and is the result of a temporary prothrombotic state.9 The half-life of antithrombotic protein C is shorter than vitamin K–dependent prothrombotic factors II, X, and IX. Early in warfarin treatment, an acquired state of reduced protein C level exists, which can lead to vessel thrombosis and subsequent cutaneous necrosis. Treatment of warfarin-induced skin necrosis involves cessation of warfarin, supplementation with vitamin K to reverse the effects of warfarin, and the initiation of heparin or low-molecular-weight heparin.⁹

The Diagnosis: Calciphylaxis

Histopathology revealed epidermal and dermal necrosis, a perivascular neutrophilic infiltrate, and scattered microcalcifications within small- and medium-sized subcutaneous vessels, consistent with a diagnosis of calciphylaxis (Figure). Calciphylaxis (also known as calcific uremic arteriolopathy) is a rare, severe, and often fatal vasculopathy that predominately occurs in patients with end-stage renal failure.¹ The pathogenesis of calciphylaxis remains poorly understood; however, it generally is thought that an imbalance in calcium homeostasis in susceptible hosts results in the precipitation of calcium phosphate within vessel walls leading to endothelial damage with subsequent thrombotic vasculopathy and ischemic tissue damage. Acquired and congenital hypercoagulable states have been implicated in the pathogenesis of calciphylaxis.²

Treatment of calciphylaxis is directed at normalizing abnormal calcium metabolism; removing possible exacerbating agents, such as warfarin, systemic corticosteroids, calcium, and iron; and transitioning patients with end-stage renal disease to hemodialysis, if not already initiated. The treatment approach is multifaceted, and numerous therapies usually are attempted simultaneously. Vitamin K supplementation, low-calcium dialysate, non–calcium carbonate phosphate binders, cinacalcet, becaplermin, bisphosphonates, hyperbaric oxygen, and intravenous sodium thiosulfate all have been utilized with some success. Currently, intravenous sodium thiosulfate is the mainstay therapy for the treatment of calciphylaxis.² Although the mechanism of sodium thiosulfate is not entirely understood, it is known to have anticalcification, vasodilatory, and antioxidant properties.

Retiform purpura clinically is characterized by reticulated, branching, purpuric skin lesions. It occurs following vascular insult by way of vessel lumen occlusion (thrombotic vasculopathy) and less frequently by vessel wall inflammation (vasculitis). The differential diagnosis for retiform purpura includes various causes of microvascular occlusion, including hypercoagulable states and type I cryoglobulinemia, calciphylaxis, infections, autoimmune vasculitic conditions, and embolic causes.³

Cutaneous disease in individuals with antiphospholipid antibodies may present similarly with retiform purpura in the form of necrotizing livedo reticularis, leg ulcers, or widespread cutaneous necrosis. Histopathologic findings include vascular thrombi with partial or complete obstruction of the small- to medium-sized arteries at the dermoepidermal junction, often in the absence of an inflammatory infiltrate.⁴ True vasculitis is not typical of antiphospholipid syndrome.

Medium vessel vasculitides, such as polyarteritis nodosa, clinically present with livedo reticularis, subcutaneous nodules, and tissue necrosis. Dermatopathologic evaluation of a medium-sized vessel vasculitis would demonstrate a neutrophilic vasculitis involving vessels within the deep dermis and septa of subcutaneous fat.⁵ Tissue sampling should be deep and wide enough to visualize the pathology, as shallow biopsies may show intraluminal thrombi of the superficial dermal plexus only, while a narrow specimen may result in falsenegative findings due to the focal nature of vessel involvement in conditions such as polyarteritis nodosa.

Type I cryoglobulinemia often is a manifestation of plasma cell dyscrasia and commonly presents with Raynaud phenomenon, livedo reticularis, and acrocyanosis of helices⁶ ; pathology demonstrates vessel occlusion and erythrocyte extravasation. In contrast, types II and III, also known as mixed cryoglobulinemia, are associated with hepatitis C and autoimmune connective tissue disease. They clinically present as purpuric plaques and nodules that have a propensity to vesiculate and ulcerate.⁷ Histopathologically, features of leukocytoclastic vasculitis are seen, and direct immunofluorescence demonstrates perivascular granular deposits consisting predominantly of IgM and C3 in the papillary dermis.⁸

Warfarin therapy, particularly in high initial doses, can induce lesions of cutaneous necrosis, which clinically may resemble the appearance of calciphylaxis. Warfarininduced skin necrosis typically occurs 3 to 5 days after the initiation of therapy and is the result of a temporary prothrombotic state.9 The half-life of antithrombotic protein C is shorter than vitamin K–dependent prothrombotic factors II, X, and IX. Early in warfarin treatment, an acquired state of reduced protein C level exists, which can lead to vessel thrombosis and subsequent cutaneous necrosis. Treatment of warfarin-induced skin necrosis involves cessation of warfarin, supplementation with vitamin K to reverse the effects of warfarin, and the initiation of heparin or low-molecular-weight heparin.⁹

The Diagnosis: Calciphylaxis

Histopathology revealed epidermal and dermal necrosis, a perivascular neutrophilic infiltrate, and scattered microcalcifications within small- and medium-sized subcutaneous vessels, consistent with a diagnosis of calciphylaxis (Figure). Calciphylaxis (also known as calcific uremic arteriolopathy) is a rare, severe, and often fatal vasculopathy that predominately occurs in patients with end-stage renal failure.¹ The pathogenesis of calciphylaxis remains poorly understood; however, it generally is thought that an imbalance in calcium homeostasis in susceptible hosts results in the precipitation of calcium phosphate within vessel walls leading to endothelial damage with subsequent thrombotic vasculopathy and ischemic tissue damage. Acquired and congenital hypercoagulable states have been implicated in the pathogenesis of calciphylaxis.²

Treatment of calciphylaxis is directed at normalizing abnormal calcium metabolism; removing possible exacerbating agents, such as warfarin, systemic corticosteroids, calcium, and iron; and transitioning patients with end-stage renal disease to hemodialysis, if not already initiated. The treatment approach is multifaceted, and numerous therapies usually are attempted simultaneously. Vitamin K supplementation, low-calcium dialysate, non–calcium carbonate phosphate binders, cinacalcet, becaplermin, bisphosphonates, hyperbaric oxygen, and intravenous sodium thiosulfate all have been utilized with some success. Currently, intravenous sodium thiosulfate is the mainstay therapy for the treatment of calciphylaxis.² Although the mechanism of sodium thiosulfate is not entirely understood, it is known to have anticalcification, vasodilatory, and antioxidant properties.

Retiform purpura clinically is characterized by reticulated, branching, purpuric skin lesions. It occurs following vascular insult by way of vessel lumen occlusion (thrombotic vasculopathy) and less frequently by vessel wall inflammation (vasculitis). The differential diagnosis for retiform purpura includes various causes of microvascular occlusion, including hypercoagulable states and type I cryoglobulinemia, calciphylaxis, infections, autoimmune vasculitic conditions, and embolic causes.³

Cutaneous disease in individuals with antiphospholipid antibodies may present similarly with retiform purpura in the form of necrotizing livedo reticularis, leg ulcers, or widespread cutaneous necrosis. Histopathologic findings include vascular thrombi with partial or complete obstruction of the small- to medium-sized arteries at the dermoepidermal junction, often in the absence of an inflammatory infiltrate.⁴ True vasculitis is not typical of antiphospholipid syndrome.

Medium vessel vasculitides, such as polyarteritis nodosa, clinically present with livedo reticularis, subcutaneous nodules, and tissue necrosis. Dermatopathologic evaluation of a medium-sized vessel vasculitis would demonstrate a neutrophilic vasculitis involving vessels within the deep dermis and septa of subcutaneous fat.⁵ Tissue sampling should be deep and wide enough to visualize the pathology, as shallow biopsies may show intraluminal thrombi of the superficial dermal plexus only, while a narrow specimen may result in falsenegative findings due to the focal nature of vessel involvement in conditions such as polyarteritis nodosa.

Type I cryoglobulinemia often is a manifestation of plasma cell dyscrasia and commonly presents with Raynaud phenomenon, livedo reticularis, and acrocyanosis of helices⁶ ; pathology demonstrates vessel occlusion and erythrocyte extravasation. In contrast, types II and III, also known as mixed cryoglobulinemia, are associated with hepatitis C and autoimmune connective tissue disease. They clinically present as purpuric plaques and nodules that have a propensity to vesiculate and ulcerate.⁷ Histopathologically, features of leukocytoclastic vasculitis are seen, and direct immunofluorescence demonstrates perivascular granular deposits consisting predominantly of IgM and C3 in the papillary dermis.⁸

Warfarin therapy, particularly in high initial doses, can induce lesions of cutaneous necrosis, which clinically may resemble the appearance of calciphylaxis. Warfarininduced skin necrosis typically occurs 3 to 5 days after the initiation of therapy and is the result of a temporary prothrombotic state.9 The half-life of antithrombotic protein C is shorter than vitamin K–dependent prothrombotic factors II, X, and IX. Early in warfarin treatment, an acquired state of reduced protein C level exists, which can lead to vessel thrombosis and subsequent cutaneous necrosis. Treatment of warfarin-induced skin necrosis involves cessation of warfarin, supplementation with vitamin K to reverse the effects of warfarin, and the initiation of heparin or low-molecular-weight heparin.⁹

The Diagnosis: Condyloma Latum

A punch biopsy of the perianal mass revealed epidermal acanthosis with elongated slender rete ridges, scattered intraepidermal neutrophils, and a dense dermal inflammatory infiltrate (Figure, A) with a prominent plasma cell component (Figure, B). A treponemal immunohistochemical stain revealed numerous coiled spirochetes concentrated in the lower epidermis (Figure, C). Serologic test results including rapid plasma reagin (titer 1:1024) and Treponema pallidum antibody were reactive, confirming the diagnosis of secondary syphilis with condyloma latum. The patient was treated with intramuscular penicillin G with resolution of the lesion 2 weeks later.

Syphilis, a sexually transmitted infection caused by the spirochete T pallidum, reached historically low rates in the United States in the early 2000s due to the widespread use of penicillin and effective public health efforts.1 However, the rates of primary and secondary syphilis infections recently have markedly increased, resulting in the current epidemic of syphilis in the United States and Europe.^1,2 Its wide variety of clinical and histopathologic manifestations make recognition challenging and lend it the moniker “the great imitator.”

Secondary syphilis results from the systemic spread of T pallidum and classically is characterized by the triad of a skin rash that frequently involves the palms and soles, mucosal ulceration such as condyloma latum, and lymphadenopathy.^2,3 However, condyloma latum may represent the only manifestation of secondary syphilis in a subset of patients,⁴ as observed in our patient.

In the 2 months prior to diagnosis, our patient was evaluated at multiple emergency departments and primary care clinics, receiving diagnoses of condyloma acuminatum, genital herpes simplex virus, hemorrhoids, and suspicion for malignancy—entities that comprise the differential diagnosis for condyloma latum.^2,5 Despite some degree of overlap in patient populations, risk factors, and presentations between these diagnostic considerations, recognition of certain clinical features, in addition to histopathologic evaluation, may facilitate navigation of this differential diagnosis.

Primary and secondary syphilis infections have been predominantly observed in men, mostly men who have sex with men and/or those who are infected with HIV.¹ Condyloma acuminata, genital herpes simplex virus, and chancroid also are seen in younger individuals, more commonly in those with multiple sexual partners, but show a more even gender distribution and are not restricted to those partaking in anal intercourse. The clinical presentation of condyloma latum can be differentiated by its painless, flat, smooth, and commonly hypopigmented appearance, often with associated surface erosion and a gray exudate, in contrast to condyloma acuminatum, which typically presents as nontender, flesh-colored or hyperpigmented, exophytic papules that may coalesce into plaques.^2,3,6 Genital herpes simplex virus infection presents with multiple small papulovesicular lesions with ulceration, most commonly on the tip or shaft of the penis, though perianal lesions may be seen in men who have sex with men.⁷ Similarly, chancroid presents with painful necrotizing genital ulcers most commonly on the penis, though perianal lesions also may be seen.8 Hemorrhoids classically are seen in middle-aged adults with a history of constipation, present with rectal bleeding, and may be associated with pain in the setting of thrombosis or ulceration.⁹ Finally, perianal squamous cell carcinoma primarily occurs in older adults, typically in the sixth decade of life. Verrucous carcinoma most commonly arises in the oropharynx or anogenital region in sites of chronic irritation and presents as a slow-growing exophytic mass. Classic squamous cell carcinoma most commonly occurs in association with human papillomavirus infection and presents with scaly erythematous papules or plaques.¹⁰

Our case highlighted the clinical difficulty in recognizing condyloma latum, as this lesion remained undiagnosed for 2 months, and our patient presumptively was treated for multiple perianal pathologies prior to a biopsy being performed. Due to the clinical similarity of various perianal lesions, the diagnosis of condyloma latum should be considered, and serologic studies should be performed in fitting clinical contexts, especially in light of recently rising rates of syphilis infection.^1,2

The Diagnosis: Condyloma Latum

A punch biopsy of the perianal mass revealed epidermal acanthosis with elongated slender rete ridges, scattered intraepidermal neutrophils, and a dense dermal inflammatory infiltrate (Figure, A) with a prominent plasma cell component (Figure, B). A treponemal immunohistochemical stain revealed numerous coiled spirochetes concentrated in the lower epidermis (Figure, C). Serologic test results including rapid plasma reagin (titer 1:1024) and Treponema pallidum antibody were reactive, confirming the diagnosis of secondary syphilis with condyloma latum. The patient was treated with intramuscular penicillin G with resolution of the lesion 2 weeks later.

Syphilis, a sexually transmitted infection caused by the spirochete T pallidum, reached historically low rates in the United States in the early 2000s due to the widespread use of penicillin and effective public health efforts.1 However, the rates of primary and secondary syphilis infections recently have markedly increased, resulting in the current epidemic of syphilis in the United States and Europe.^1,2 Its wide variety of clinical and histopathologic manifestations make recognition challenging and lend it the moniker “the great imitator.”

Secondary syphilis results from the systemic spread of T pallidum and classically is characterized by the triad of a skin rash that frequently involves the palms and soles, mucosal ulceration such as condyloma latum, and lymphadenopathy.^2,3 However, condyloma latum may represent the only manifestation of secondary syphilis in a subset of patients,⁴ as observed in our patient.

In the 2 months prior to diagnosis, our patient was evaluated at multiple emergency departments and primary care clinics, receiving diagnoses of condyloma acuminatum, genital herpes simplex virus, hemorrhoids, and suspicion for malignancy—entities that comprise the differential diagnosis for condyloma latum.^2,5 Despite some degree of overlap in patient populations, risk factors, and presentations between these diagnostic considerations, recognition of certain clinical features, in addition to histopathologic evaluation, may facilitate navigation of this differential diagnosis.

Primary and secondary syphilis infections have been predominantly observed in men, mostly men who have sex with men and/or those who are infected with HIV.¹ Condyloma acuminata, genital herpes simplex virus, and chancroid also are seen in younger individuals, more commonly in those with multiple sexual partners, but show a more even gender distribution and are not restricted to those partaking in anal intercourse. The clinical presentation of condyloma latum can be differentiated by its painless, flat, smooth, and commonly hypopigmented appearance, often with associated surface erosion and a gray exudate, in contrast to condyloma acuminatum, which typically presents as nontender, flesh-colored or hyperpigmented, exophytic papules that may coalesce into plaques.^2,3,6 Genital herpes simplex virus infection presents with multiple small papulovesicular lesions with ulceration, most commonly on the tip or shaft of the penis, though perianal lesions may be seen in men who have sex with men.⁷ Similarly, chancroid presents with painful necrotizing genital ulcers most commonly on the penis, though perianal lesions also may be seen.8 Hemorrhoids classically are seen in middle-aged adults with a history of constipation, present with rectal bleeding, and may be associated with pain in the setting of thrombosis or ulceration.⁹ Finally, perianal squamous cell carcinoma primarily occurs in older adults, typically in the sixth decade of life. Verrucous carcinoma most commonly arises in the oropharynx or anogenital region in sites of chronic irritation and presents as a slow-growing exophytic mass. Classic squamous cell carcinoma most commonly occurs in association with human papillomavirus infection and presents with scaly erythematous papules or plaques.¹⁰

Our case highlighted the clinical difficulty in recognizing condyloma latum, as this lesion remained undiagnosed for 2 months, and our patient presumptively was treated for multiple perianal pathologies prior to a biopsy being performed. Due to the clinical similarity of various perianal lesions, the diagnosis of condyloma latum should be considered, and serologic studies should be performed in fitting clinical contexts, especially in light of recently rising rates of syphilis infection.^1,2

The Diagnosis: Condyloma Latum

A punch biopsy of the perianal mass revealed epidermal acanthosis with elongated slender rete ridges, scattered intraepidermal neutrophils, and a dense dermal inflammatory infiltrate (Figure, A) with a prominent plasma cell component (Figure, B). A treponemal immunohistochemical stain revealed numerous coiled spirochetes concentrated in the lower epidermis (Figure, C). Serologic test results including rapid plasma reagin (titer 1:1024) and Treponema pallidum antibody were reactive, confirming the diagnosis of secondary syphilis with condyloma latum. The patient was treated with intramuscular penicillin G with resolution of the lesion 2 weeks later.

Syphilis, a sexually transmitted infection caused by the spirochete T pallidum, reached historically low rates in the United States in the early 2000s due to the widespread use of penicillin and effective public health efforts.1 However, the rates of primary and secondary syphilis infections recently have markedly increased, resulting in the current epidemic of syphilis in the United States and Europe.^1,2 Its wide variety of clinical and histopathologic manifestations make recognition challenging and lend it the moniker “the great imitator.”

Secondary syphilis results from the systemic spread of T pallidum and classically is characterized by the triad of a skin rash that frequently involves the palms and soles, mucosal ulceration such as condyloma latum, and lymphadenopathy.^2,3 However, condyloma latum may represent the only manifestation of secondary syphilis in a subset of patients,⁴ as observed in our patient.

In the 2 months prior to diagnosis, our patient was evaluated at multiple emergency departments and primary care clinics, receiving diagnoses of condyloma acuminatum, genital herpes simplex virus, hemorrhoids, and suspicion for malignancy—entities that comprise the differential diagnosis for condyloma latum.^2,5 Despite some degree of overlap in patient populations, risk factors, and presentations between these diagnostic considerations, recognition of certain clinical features, in addition to histopathologic evaluation, may facilitate navigation of this differential diagnosis.

Primary and secondary syphilis infections have been predominantly observed in men, mostly men who have sex with men and/or those who are infected with HIV.¹ Condyloma acuminata, genital herpes simplex virus, and chancroid also are seen in younger individuals, more commonly in those with multiple sexual partners, but show a more even gender distribution and are not restricted to those partaking in anal intercourse. The clinical presentation of condyloma latum can be differentiated by its painless, flat, smooth, and commonly hypopigmented appearance, often with associated surface erosion and a gray exudate, in contrast to condyloma acuminatum, which typically presents as nontender, flesh-colored or hyperpigmented, exophytic papules that may coalesce into plaques.^2,3,6 Genital herpes simplex virus infection presents with multiple small papulovesicular lesions with ulceration, most commonly on the tip or shaft of the penis, though perianal lesions may be seen in men who have sex with men.⁷ Similarly, chancroid presents with painful necrotizing genital ulcers most commonly on the penis, though perianal lesions also may be seen.8 Hemorrhoids classically are seen in middle-aged adults with a history of constipation, present with rectal bleeding, and may be associated with pain in the setting of thrombosis or ulceration.⁹ Finally, perianal squamous cell carcinoma primarily occurs in older adults, typically in the sixth decade of life. Verrucous carcinoma most commonly arises in the oropharynx or anogenital region in sites of chronic irritation and presents as a slow-growing exophytic mass. Classic squamous cell carcinoma most commonly occurs in association with human papillomavirus infection and presents with scaly erythematous papules or plaques.¹⁰

Our case highlighted the clinical difficulty in recognizing condyloma latum, as this lesion remained undiagnosed for 2 months, and our patient presumptively was treated for multiple perianal pathologies prior to a biopsy being performed. Due to the clinical similarity of various perianal lesions, the diagnosis of condyloma latum should be considered, and serologic studies should be performed in fitting clinical contexts, especially in light of recently rising rates of syphilis infection.^1,2

The Diagnosis: Pseudomonas Pyoderma

A skin swab confirmed the presence of a ciprofloxacinsusceptible Pseudomonas aeruginosa strain. Our patient received oral ciprofloxacin 500 mg twice daily for 10 days with remarkable clinical improvement. The remaining skin lesion was successfully treated with more frequent diaper changes and the use of topical corticosteroids and emollients.

The topographical location, cutaneous morphology, clinical context, and sometimes the type of exudate are fundamental for the diagnosis of eruptions in intertriginous areas. Cutaneous Candida infections are common in these locations. They classically present as markedly erythematous plaques that occasionally are erosive, accompanied by satellite papules and pustules.¹ Tinea cruris is a dermatophyte infection of the groin, proximal medial thighs, perineum, and buttocks. It usually presents as an erythematous patch that spreads centrifugally with partial central clearing and a slightly elevated, scaly border. Although candidiasis was higher on the differential, it was less likely, as our patient had a concomitant exudate inconsistent with Candida infections. Also, the lack of response to antifungal agents made hypotheses of fungal infections improbable.¹

Inverse psoriasis is a variant of psoriasis identified by the development of well-demarcated, nonscaly, shiny plaques on body folds.² Psoriasis is a chronic disease with several other cutaneous manifestations, such as nail and scalp involvement, as well as erythematous scaly plaques on the extensor surfaces of the limbs. The absence of a history of psoriasis, lack of other cutaneous manifestations, and no response to topical corticosteroids made the diagnosis of inverse psoriasis unlikely in our patient.

Erythrasma is a common superficial cutaneous infection caused by Corynebacterium minutissimum, a grampositive bacillus. It typically presents as an intertriginous eruption characterized by small erythematous to brown patches or thin plaques with fine scaling and sharp borders.³ Erythrasma displays a coral red fluorescence on Wood lamp examination that can be useful in the distinction from other causes of intertrigo.¹ Although this examination had not been performed in our patient, the striking exudate made erythrasma less likely, and the culture performed on skin swab material would help to rule out this diagnosis.

Pseudomonas aeruginosa is a gram-negative strict aerobic bacillus of ubiquitous distribution with a preference for humid environments.^4,5Pseudomonas aeruginosa infections were first reported in the 19th century by physicians who noticed a peculiar odorous condition that caused a blue-green discoloration on bandages. This coloration explains the species name aeruginosa which is derived from the Latin word for copper rust.⁴ It comes from several water-soluble pigments produced by this microorganism, the most prevalent of which are pyocyanin and pyoverdine. Pyocyanin has a greenish-blue color and is nonfluorescent, while pyoverdine is green-yellowish and fluoresces under Wood light.⁵ Other pigments, such as pyorubin and pyomelanin, can be produced by some Pseudomonas strains.⁴

Pseudomonas aeruginosa has become one of the main pathogens involved in hospital-acquired infections,⁶ especially in immunocompromised patients.^6,7 It is a frequent cause of respiratory infections in patients with cystic fibrosis, as it is present in the airways of up to 70% of these patients in adulthood.⁷ Also, due to a variety of adaptive mechanisms with the development of resistance to a range of antibiotics, P aeruginosa has become a worldwide public health problem and is involved in several life-threatening nosocomial infections.^7,8

Cutaneous P aeruginosa infections range from superficial to deep tissue involvement and can affect both immunocompromised and immunocompetent individuals.⁹ They are classified as primary when they originate directly from the skin or secondary when they occur in the context of bacteremia. Primary infections mostly are mild and often are seen in healthy individuals; they usually occur by inoculation and predominate in moist areas where skin breakdown is frequent. Secondary infections typically affect immunocompromised individuals and portend a poor prognosis.^5,9

Denominated as Pseudomonas pyoderma, the superficial skin infection by P aeruginosa is described as a condition where the epidermis has a moth-eaten appearance with macerated or eroded borders.¹⁰ A blue-greenish exudate and a grape juice odor often are present. This infection usually occurs as a complication of several skin conditions such as tinea pedis, eczema, burns, wounds, and ulcers.^5,10

We believe that our patient developed Pseudomonas pyoderma as a complication of diaper dermatitis. His extended hospital stay with the use of different antibiotic regimens for the treatment of several infectious complications may have contributed to the development of infection by P aeruginosa.¹¹ Despite its great clinical relevance, there are few studies in the literature on primary skin infections caused by P aeruginosa, and clinical descriptions with images are rare. Our patient had a nonspecific noneczematous dermatitis, and the projections on the periphery of the lesion resembled the moth-eaten appearance of the classic description of Pseudomonas pyoderma.^5,10 The presence of a greenish exudate should promptly raise suspicion for this entity. We believe that the presentation of this case can illustrate this finding and help physicians to recognize this infection.

The Diagnosis: Pseudomonas Pyoderma

A skin swab confirmed the presence of a ciprofloxacinsusceptible Pseudomonas aeruginosa strain. Our patient received oral ciprofloxacin 500 mg twice daily for 10 days with remarkable clinical improvement. The remaining skin lesion was successfully treated with more frequent diaper changes and the use of topical corticosteroids and emollients.

The topographical location, cutaneous morphology, clinical context, and sometimes the type of exudate are fundamental for the diagnosis of eruptions in intertriginous areas. Cutaneous Candida infections are common in these locations. They classically present as markedly erythematous plaques that occasionally are erosive, accompanied by satellite papules and pustules.¹ Tinea cruris is a dermatophyte infection of the groin, proximal medial thighs, perineum, and buttocks. It usually presents as an erythematous patch that spreads centrifugally with partial central clearing and a slightly elevated, scaly border. Although candidiasis was higher on the differential, it was less likely, as our patient had a concomitant exudate inconsistent with Candida infections. Also, the lack of response to antifungal agents made hypotheses of fungal infections improbable.¹

Inverse psoriasis is a variant of psoriasis identified by the development of well-demarcated, nonscaly, shiny plaques on body folds.² Psoriasis is a chronic disease with several other cutaneous manifestations, such as nail and scalp involvement, as well as erythematous scaly plaques on the extensor surfaces of the limbs. The absence of a history of psoriasis, lack of other cutaneous manifestations, and no response to topical corticosteroids made the diagnosis of inverse psoriasis unlikely in our patient.

Erythrasma is a common superficial cutaneous infection caused by Corynebacterium minutissimum, a grampositive bacillus. It typically presents as an intertriginous eruption characterized by small erythematous to brown patches or thin plaques with fine scaling and sharp borders.³ Erythrasma displays a coral red fluorescence on Wood lamp examination that can be useful in the distinction from other causes of intertrigo.¹ Although this examination had not been performed in our patient, the striking exudate made erythrasma less likely, and the culture performed on skin swab material would help to rule out this diagnosis.

Pseudomonas aeruginosa is a gram-negative strict aerobic bacillus of ubiquitous distribution with a preference for humid environments.^4,5Pseudomonas aeruginosa infections were first reported in the 19th century by physicians who noticed a peculiar odorous condition that caused a blue-green discoloration on bandages. This coloration explains the species name aeruginosa which is derived from the Latin word for copper rust.⁴ It comes from several water-soluble pigments produced by this microorganism, the most prevalent of which are pyocyanin and pyoverdine. Pyocyanin has a greenish-blue color and is nonfluorescent, while pyoverdine is green-yellowish and fluoresces under Wood light.⁵ Other pigments, such as pyorubin and pyomelanin, can be produced by some Pseudomonas strains.⁴

Pseudomonas aeruginosa has become one of the main pathogens involved in hospital-acquired infections,⁶ especially in immunocompromised patients.^6,7 It is a frequent cause of respiratory infections in patients with cystic fibrosis, as it is present in the airways of up to 70% of these patients in adulthood.⁷ Also, due to a variety of adaptive mechanisms with the development of resistance to a range of antibiotics, P aeruginosa has become a worldwide public health problem and is involved in several life-threatening nosocomial infections.^7,8

Cutaneous P aeruginosa infections range from superficial to deep tissue involvement and can affect both immunocompromised and immunocompetent individuals.⁹ They are classified as primary when they originate directly from the skin or secondary when they occur in the context of bacteremia. Primary infections mostly are mild and often are seen in healthy individuals; they usually occur by inoculation and predominate in moist areas where skin breakdown is frequent. Secondary infections typically affect immunocompromised individuals and portend a poor prognosis.^5,9

Denominated as Pseudomonas pyoderma, the superficial skin infection by P aeruginosa is described as a condition where the epidermis has a moth-eaten appearance with macerated or eroded borders.¹⁰ A blue-greenish exudate and a grape juice odor often are present. This infection usually occurs as a complication of several skin conditions such as tinea pedis, eczema, burns, wounds, and ulcers.^5,10

We believe that our patient developed Pseudomonas pyoderma as a complication of diaper dermatitis. His extended hospital stay with the use of different antibiotic regimens for the treatment of several infectious complications may have contributed to the development of infection by P aeruginosa.¹¹ Despite its great clinical relevance, there are few studies in the literature on primary skin infections caused by P aeruginosa, and clinical descriptions with images are rare. Our patient had a nonspecific noneczematous dermatitis, and the projections on the periphery of the lesion resembled the moth-eaten appearance of the classic description of Pseudomonas pyoderma.^5,10 The presence of a greenish exudate should promptly raise suspicion for this entity. We believe that the presentation of this case can illustrate this finding and help physicians to recognize this infection.

The Diagnosis: Pseudomonas Pyoderma

A skin swab confirmed the presence of a ciprofloxacinsusceptible Pseudomonas aeruginosa strain. Our patient received oral ciprofloxacin 500 mg twice daily for 10 days with remarkable clinical improvement. The remaining skin lesion was successfully treated with more frequent diaper changes and the use of topical corticosteroids and emollients.

The topographical location, cutaneous morphology, clinical context, and sometimes the type of exudate are fundamental for the diagnosis of eruptions in intertriginous areas. Cutaneous Candida infections are common in these locations. They classically present as markedly erythematous plaques that occasionally are erosive, accompanied by satellite papules and pustules.¹ Tinea cruris is a dermatophyte infection of the groin, proximal medial thighs, perineum, and buttocks. It usually presents as an erythematous patch that spreads centrifugally with partial central clearing and a slightly elevated, scaly border. Although candidiasis was higher on the differential, it was less likely, as our patient had a concomitant exudate inconsistent with Candida infections. Also, the lack of response to antifungal agents made hypotheses of fungal infections improbable.¹

Inverse psoriasis is a variant of psoriasis identified by the development of well-demarcated, nonscaly, shiny plaques on body folds.² Psoriasis is a chronic disease with several other cutaneous manifestations, such as nail and scalp involvement, as well as erythematous scaly plaques on the extensor surfaces of the limbs. The absence of a history of psoriasis, lack of other cutaneous manifestations, and no response to topical corticosteroids made the diagnosis of inverse psoriasis unlikely in our patient.

Erythrasma is a common superficial cutaneous infection caused by Corynebacterium minutissimum, a grampositive bacillus. It typically presents as an intertriginous eruption characterized by small erythematous to brown patches or thin plaques with fine scaling and sharp borders.³ Erythrasma displays a coral red fluorescence on Wood lamp examination that can be useful in the distinction from other causes of intertrigo.¹ Although this examination had not been performed in our patient, the striking exudate made erythrasma less likely, and the culture performed on skin swab material would help to rule out this diagnosis.

Pseudomonas aeruginosa is a gram-negative strict aerobic bacillus of ubiquitous distribution with a preference for humid environments.^4,5Pseudomonas aeruginosa infections were first reported in the 19th century by physicians who noticed a peculiar odorous condition that caused a blue-green discoloration on bandages. This coloration explains the species name aeruginosa which is derived from the Latin word for copper rust.⁴ It comes from several water-soluble pigments produced by this microorganism, the most prevalent of which are pyocyanin and pyoverdine. Pyocyanin has a greenish-blue color and is nonfluorescent, while pyoverdine is green-yellowish and fluoresces under Wood light.⁵ Other pigments, such as pyorubin and pyomelanin, can be produced by some Pseudomonas strains.⁴

Pseudomonas aeruginosa has become one of the main pathogens involved in hospital-acquired infections,⁶ especially in immunocompromised patients.^6,7 It is a frequent cause of respiratory infections in patients with cystic fibrosis, as it is present in the airways of up to 70% of these patients in adulthood.⁷ Also, due to a variety of adaptive mechanisms with the development of resistance to a range of antibiotics, P aeruginosa has become a worldwide public health problem and is involved in several life-threatening nosocomial infections.^7,8

Cutaneous P aeruginosa infections range from superficial to deep tissue involvement and can affect both immunocompromised and immunocompetent individuals.⁹ They are classified as primary when they originate directly from the skin or secondary when they occur in the context of bacteremia. Primary infections mostly are mild and often are seen in healthy individuals; they usually occur by inoculation and predominate in moist areas where skin breakdown is frequent. Secondary infections typically affect immunocompromised individuals and portend a poor prognosis.^5,9

Denominated as Pseudomonas pyoderma, the superficial skin infection by P aeruginosa is described as a condition where the epidermis has a moth-eaten appearance with macerated or eroded borders.¹⁰ A blue-greenish exudate and a grape juice odor often are present. This infection usually occurs as a complication of several skin conditions such as tinea pedis, eczema, burns, wounds, and ulcers.^5,10

We believe that our patient developed Pseudomonas pyoderma as a complication of diaper dermatitis. His extended hospital stay with the use of different antibiotic regimens for the treatment of several infectious complications may have contributed to the development of infection by P aeruginosa.¹¹ Despite its great clinical relevance, there are few studies in the literature on primary skin infections caused by P aeruginosa, and clinical descriptions with images are rare. Our patient had a nonspecific noneczematous dermatitis, and the projections on the periphery of the lesion resembled the moth-eaten appearance of the classic description of Pseudomonas pyoderma.^5,10 The presence of a greenish exudate should promptly raise suspicion for this entity. We believe that the presentation of this case can illustrate this finding and help physicians to recognize this infection.

The Diagnosis: Epidermolysis Bullosa

Our patient was found to have epidermolysis bullosa (EB), a rare genetic disease in which the superficial layers of the skin separate to form vesicles or bullae due to a mutation in the keratin 14 gene, KRT14. Separation of the skin occurs due to cleavage of various proteins that connect the epidermis to the dermis. A genetic mutation in KRT14, one of the more common genetic mutations associated with EB, results in cleavage at the basal epidermal protein keratin 14. The skin of individuals with EB typically is fragile and cannot tolerate friction or manipulation due to the risk for new bullae formation.¹ Epidermolysis bullosa is rare, affecting approximately 20 children per 1 million births in the United States, and is not commonly seen by most general adult dermatologists.²

In our patient, the differential diagnoses included staphylococcal scalded skin syndrome (SSSS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), herpes simplex virus (HSV), and bullous pemphigoid (BP). Symptoms of SSSS can range from mild and localized to full-body exfoliation of the skin. Although SSSS can resemble other bullous disorders, its etiology arises from the Staphylococcus exotoxin targeting desmoglein in the stratum granulosum— the layer of the epidermis between the stratum corneum and stratum spinosum.³ Lesions start on the face, neck, and body folds, which was consistent with our patient’s presentation. However, bullae continued to develop in our patient despite antibiotic therapy, which reduced the likelihood of SSSS. Stevens-Johnson syndrome/toxic epidermal necrolysis develops rapidly and often involves the mucosa, which our patient initially did not have. In children, SJS/TEN can develop secondary to infection, whereas in adults it more commonly is associated with medication administration.⁴ Although the mother tested negative for HSV, the infant was started on acyclovir, which ultimately was discontinued due to low clinical suspicion. The clinical presentation of HSV (ie, clustered vesicles) was not consistent with our patient’s presentation. Bullous pemphigoid is a subepithelial blistering disease seen in older adults. Tense, fluidfilled blisters primarily are seen on the trunk and flexures. Although infantile BP can occur, it usually does not present in the neonatal period but rather at approximately 3 to 5 months of age.⁵

High clinical suspicion for EB due to the common characteristics of bullae location and formation following skin manipulation led to genetic testing in our patient. Mild forms of EB simplex typically appear on the upper and lower extremities with sparing of the trunk. In more severe cases of EB simplex, truncal and mucosal involvement may occur.⁶ In our case, the infant had a classic distribution of arm and leg blisters with truncal sparing. Epidermolysis bullosa may not be diagnosed in the neonatal period because of its similarities to other more common diseases, such as HSV or bullous impetigo, or other genetic blistering diseases, such as epidermolytic ichthyosis and incontinentia pigmenti.⁶

Epidermolysis bullosa can be inherited in an autosomal-dominant or autosomal-recessive fashion or with de novo mutations and is classified based on the location of cleavage in the skin. The 4 classical subtypes— simplex, junctional, dystrophic, and Kindler—have now been further subclassified. Epidermolysis bullosa simplex (intraepidermal split) is now separated into basal and suprabasal, with further subclassification including the distribution of blisters (generalized or localized) and the severity of cutaneous or extracutaneous involvement.⁷

In our case, the infant was found to have intraepidermal EB (simplex) due to a KRT14 mutation (missense mutation).⁶KRT14 (17q21.2) and KRT5 (12q13.3) are the 2 most common mutations causing cleavage at the basal intraepidermal layer. Thickening of the palms, soles, and nails can be seen; however, blisters heal well without scarring, as seen in our patient. Junctional EB due to cleavage at the intralamina lucida often involves mutations in laminin 332, plectin, and α6β4 integrin. Infants with junctional EB often die from severe infection, dehydration, or malnutrition due to mucosal involvement. Dystrophic EB occurs due to a collagen VII mutation in the dermis, leading to blisters at the sublamina densa and more severe symptoms in the recessive form.⁷

Newborn management for infants with EB differs from normal newborn care due to increased skin fragility with physical manipulation. Minimal skin manipulation and proper wound care are essential from the first day of life. For new bullae formation, bullae should be ruptured with a needle at the base of the blister and drained. The remaining skin overlying the wound should remain in place as a natural wound barrier. Patients with EB should not have tape or adhesive bandages applied directly to the skin. Instead, nonadhesive dressings can be placed directly on wounds and covered in soft wraps circumferentially. Dressings can be taped together without involving the skin. The cost for supplies for families to manage bullae is expensive. Fortunately, there are resources available for supplies and support for families, including the EB Research Partnership (https://www.ebresearch.org/) and DEBRA of America (https://www.debra.org/).

Currently, there is no cure for EB. Current treatment involves wound care, prevention, and symptomatic relief. Prevention includes avoiding activities that may result in increased friction of the skin and ensuring careful manipulation. Children with EB may have pain or itching from their blisters, which can be treated with oral acetaminophen or ibuprofen and diphenhydramine, respectively. Other complications of EB include anemia, dehydration, constipation, infection, and malnutrition. In more severe forms of EB, complications including eye problems, mucosal strictures, and skin cancer may occur.⁸ Future treatment directions include gene therapy, bone marrow transplantation, protein replacement therapies, and cell-based therapies. Prognosis for infants with EB due to KRT14 mutation is good, as it is a milder subtype of EB with a full life expectancy and improvement of blistering skin with age. The most at-risk time for early death is during infancy due to increased risk for infection.⁸ In this case, our patient showed full healing with no scar formation, which suggested a reassuring prognosis.

The Diagnosis: Epidermolysis Bullosa

Our patient was found to have epidermolysis bullosa (EB), a rare genetic disease in which the superficial layers of the skin separate to form vesicles or bullae due to a mutation in the keratin 14 gene, KRT14. Separation of the skin occurs due to cleavage of various proteins that connect the epidermis to the dermis. A genetic mutation in KRT14, one of the more common genetic mutations associated with EB, results in cleavage at the basal epidermal protein keratin 14. The skin of individuals with EB typically is fragile and cannot tolerate friction or manipulation due to the risk for new bullae formation.¹ Epidermolysis bullosa is rare, affecting approximately 20 children per 1 million births in the United States, and is not commonly seen by most general adult dermatologists.²

In our patient, the differential diagnoses included staphylococcal scalded skin syndrome (SSSS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), herpes simplex virus (HSV), and bullous pemphigoid (BP). Symptoms of SSSS can range from mild and localized to full-body exfoliation of the skin. Although SSSS can resemble other bullous disorders, its etiology arises from the Staphylococcus exotoxin targeting desmoglein in the stratum granulosum— the layer of the epidermis between the stratum corneum and stratum spinosum.³ Lesions start on the face, neck, and body folds, which was consistent with our patient’s presentation. However, bullae continued to develop in our patient despite antibiotic therapy, which reduced the likelihood of SSSS. Stevens-Johnson syndrome/toxic epidermal necrolysis develops rapidly and often involves the mucosa, which our patient initially did not have. In children, SJS/TEN can develop secondary to infection, whereas in adults it more commonly is associated with medication administration.⁴ Although the mother tested negative for HSV, the infant was started on acyclovir, which ultimately was discontinued due to low clinical suspicion. The clinical presentation of HSV (ie, clustered vesicles) was not consistent with our patient’s presentation. Bullous pemphigoid is a subepithelial blistering disease seen in older adults. Tense, fluidfilled blisters primarily are seen on the trunk and flexures. Although infantile BP can occur, it usually does not present in the neonatal period but rather at approximately 3 to 5 months of age.⁵

High clinical suspicion for EB due to the common characteristics of bullae location and formation following skin manipulation led to genetic testing in our patient. Mild forms of EB simplex typically appear on the upper and lower extremities with sparing of the trunk. In more severe cases of EB simplex, truncal and mucosal involvement may occur.⁶ In our case, the infant had a classic distribution of arm and leg blisters with truncal sparing. Epidermolysis bullosa may not be diagnosed in the neonatal period because of its similarities to other more common diseases, such as HSV or bullous impetigo, or other genetic blistering diseases, such as epidermolytic ichthyosis and incontinentia pigmenti.⁶

Epidermolysis bullosa can be inherited in an autosomal-dominant or autosomal-recessive fashion or with de novo mutations and is classified based on the location of cleavage in the skin. The 4 classical subtypes— simplex, junctional, dystrophic, and Kindler—have now been further subclassified. Epidermolysis bullosa simplex (intraepidermal split) is now separated into basal and suprabasal, with further subclassification including the distribution of blisters (generalized or localized) and the severity of cutaneous or extracutaneous involvement.⁷

In our case, the infant was found to have intraepidermal EB (simplex) due to a KRT14 mutation (missense mutation).⁶KRT14 (17q21.2) and KRT5 (12q13.3) are the 2 most common mutations causing cleavage at the basal intraepidermal layer. Thickening of the palms, soles, and nails can be seen; however, blisters heal well without scarring, as seen in our patient. Junctional EB due to cleavage at the intralamina lucida often involves mutations in laminin 332, plectin, and α6β4 integrin. Infants with junctional EB often die from severe infection, dehydration, or malnutrition due to mucosal involvement. Dystrophic EB occurs due to a collagen VII mutation in the dermis, leading to blisters at the sublamina densa and more severe symptoms in the recessive form.⁷

Newborn management for infants with EB differs from normal newborn care due to increased skin fragility with physical manipulation. Minimal skin manipulation and proper wound care are essential from the first day of life. For new bullae formation, bullae should be ruptured with a needle at the base of the blister and drained. The remaining skin overlying the wound should remain in place as a natural wound barrier. Patients with EB should not have tape or adhesive bandages applied directly to the skin. Instead, nonadhesive dressings can be placed directly on wounds and covered in soft wraps circumferentially. Dressings can be taped together without involving the skin. The cost for supplies for families to manage bullae is expensive. Fortunately, there are resources available for supplies and support for families, including the EB Research Partnership (https://www.ebresearch.org/) and DEBRA of America (https://www.debra.org/).

Currently, there is no cure for EB. Current treatment involves wound care, prevention, and symptomatic relief. Prevention includes avoiding activities that may result in increased friction of the skin and ensuring careful manipulation. Children with EB may have pain or itching from their blisters, which can be treated with oral acetaminophen or ibuprofen and diphenhydramine, respectively. Other complications of EB include anemia, dehydration, constipation, infection, and malnutrition. In more severe forms of EB, complications including eye problems, mucosal strictures, and skin cancer may occur.⁸ Future treatment directions include gene therapy, bone marrow transplantation, protein replacement therapies, and cell-based therapies. Prognosis for infants with EB due to KRT14 mutation is good, as it is a milder subtype of EB with a full life expectancy and improvement of blistering skin with age. The most at-risk time for early death is during infancy due to increased risk for infection.⁸ In this case, our patient showed full healing with no scar formation, which suggested a reassuring prognosis.

The Diagnosis: Epidermolysis Bullosa

Our patient was found to have epidermolysis bullosa (EB), a rare genetic disease in which the superficial layers of the skin separate to form vesicles or bullae due to a mutation in the keratin 14 gene, KRT14. Separation of the skin occurs due to cleavage of various proteins that connect the epidermis to the dermis. A genetic mutation in KRT14, one of the more common genetic mutations associated with EB, results in cleavage at the basal epidermal protein keratin 14. The skin of individuals with EB typically is fragile and cannot tolerate friction or manipulation due to the risk for new bullae formation.¹ Epidermolysis bullosa is rare, affecting approximately 20 children per 1 million births in the United States, and is not commonly seen by most general adult dermatologists.²

In our patient, the differential diagnoses included staphylococcal scalded skin syndrome (SSSS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), herpes simplex virus (HSV), and bullous pemphigoid (BP). Symptoms of SSSS can range from mild and localized to full-body exfoliation of the skin. Although SSSS can resemble other bullous disorders, its etiology arises from the Staphylococcus exotoxin targeting desmoglein in the stratum granulosum— the layer of the epidermis between the stratum corneum and stratum spinosum.³ Lesions start on the face, neck, and body folds, which was consistent with our patient’s presentation. However, bullae continued to develop in our patient despite antibiotic therapy, which reduced the likelihood of SSSS. Stevens-Johnson syndrome/toxic epidermal necrolysis develops rapidly and often involves the mucosa, which our patient initially did not have. In children, SJS/TEN can develop secondary to infection, whereas in adults it more commonly is associated with medication administration.⁴ Although the mother tested negative for HSV, the infant was started on acyclovir, which ultimately was discontinued due to low clinical suspicion. The clinical presentation of HSV (ie, clustered vesicles) was not consistent with our patient’s presentation. Bullous pemphigoid is a subepithelial blistering disease seen in older adults. Tense, fluidfilled blisters primarily are seen on the trunk and flexures. Although infantile BP can occur, it usually does not present in the neonatal period but rather at approximately 3 to 5 months of age.⁵

High clinical suspicion for EB due to the common characteristics of bullae location and formation following skin manipulation led to genetic testing in our patient. Mild forms of EB simplex typically appear on the upper and lower extremities with sparing of the trunk. In more severe cases of EB simplex, truncal and mucosal involvement may occur.⁶ In our case, the infant had a classic distribution of arm and leg blisters with truncal sparing. Epidermolysis bullosa may not be diagnosed in the neonatal period because of its similarities to other more common diseases, such as HSV or bullous impetigo, or other genetic blistering diseases, such as epidermolytic ichthyosis and incontinentia pigmenti.⁶

Epidermolysis bullosa can be inherited in an autosomal-dominant or autosomal-recessive fashion or with de novo mutations and is classified based on the location of cleavage in the skin. The 4 classical subtypes— simplex, junctional, dystrophic, and Kindler—have now been further subclassified. Epidermolysis bullosa simplex (intraepidermal split) is now separated into basal and suprabasal, with further subclassification including the distribution of blisters (generalized or localized) and the severity of cutaneous or extracutaneous involvement.⁷

In our case, the infant was found to have intraepidermal EB (simplex) due to a KRT14 mutation (missense mutation).⁶KRT14 (17q21.2) and KRT5 (12q13.3) are the 2 most common mutations causing cleavage at the basal intraepidermal layer. Thickening of the palms, soles, and nails can be seen; however, blisters heal well without scarring, as seen in our patient. Junctional EB due to cleavage at the intralamina lucida often involves mutations in laminin 332, plectin, and α6β4 integrin. Infants with junctional EB often die from severe infection, dehydration, or malnutrition due to mucosal involvement. Dystrophic EB occurs due to a collagen VII mutation in the dermis, leading to blisters at the sublamina densa and more severe symptoms in the recessive form.⁷

Newborn management for infants with EB differs from normal newborn care due to increased skin fragility with physical manipulation. Minimal skin manipulation and proper wound care are essential from the first day of life. For new bullae formation, bullae should be ruptured with a needle at the base of the blister and drained. The remaining skin overlying the wound should remain in place as a natural wound barrier. Patients with EB should not have tape or adhesive bandages applied directly to the skin. Instead, nonadhesive dressings can be placed directly on wounds and covered in soft wraps circumferentially. Dressings can be taped together without involving the skin. The cost for supplies for families to manage bullae is expensive. Fortunately, there are resources available for supplies and support for families, including the EB Research Partnership (https://www.ebresearch.org/) and DEBRA of America (https://www.debra.org/).

Currently, there is no cure for EB. Current treatment involves wound care, prevention, and symptomatic relief. Prevention includes avoiding activities that may result in increased friction of the skin and ensuring careful manipulation. Children with EB may have pain or itching from their blisters, which can be treated with oral acetaminophen or ibuprofen and diphenhydramine, respectively. Other complications of EB include anemia, dehydration, constipation, infection, and malnutrition. In more severe forms of EB, complications including eye problems, mucosal strictures, and skin cancer may occur.⁸ Future treatment directions include gene therapy, bone marrow transplantation, protein replacement therapies, and cell-based therapies. Prognosis for infants with EB due to KRT14 mutation is good, as it is a milder subtype of EB with a full life expectancy and improvement of blistering skin with age. The most at-risk time for early death is during infancy due to increased risk for infection.⁸ In this case, our patient showed full healing with no scar formation, which suggested a reassuring prognosis.

The Diagnosis: Cutaneous B-cell Lymphoma

Shave biopsies of 3 lesions revealed a dense, diffuse, atypical lymphoid infiltrate occupying the entirety of the dermis and obscuring the dermoepidermal junction. The infiltrate consisted predominantly of largesized lymphoid cells with fine chromatin and conspicuous nucleoli (Figure). Immunohistochemistry was positive for CD45 and CD20, indicating B-cell lineage. Bcl-2, multiple myeloma oncogene 1, and forkhead box protein P1 also were expressed in the vast majority of lesional cells, distinguishing the lesion from other forms of cutaneous B-cell lymphomas.¹ These findings were consistent with large B-cell lymphoma with a high proliferation index, consistent with primary cutaneous diffuse large B-cell lymphoma, leg type, which often presents on the lower leg.² The patient had a negative systemic workup including bone marrow biopsy. He was started on the R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) chemotherapy regimen.

Primary cutaneous diffuse large B-cell lymphoma, leg type, is an intermediately aggressive and rare form of B-cell lymphoma with a poor prognosis that primarily affects elderly female patients. Primary cutaneous diffuse large B-cell lymphoma, leg type, accounts for only 1% to 3% of cutaneous lymphomas and approximately 10% to 20% of primary cutaneous B-cell lymphomas.² It typically presents as multiple red-brown or bluish nodules on the lower extremities or trunk. Presentation as a solitary nodule also is possible.^1,2 Histologic analysis of primary cutaneous diffuse large B-cell lymphoma, leg type, reveals large cells with round nuclei (immunoblasts and centroblasts), and the immunohistochemical profile shows strong Bcl-2 expression often accompanied by the multiple myeloma oncogene 1 protein.³ The 5-year survival rate is approximately 50%, which is lower than other types of primary cutaneous B-cell lymphomas, and the progression of disease is characterized by frequent relapses and involvement of extracutaneous regions such as the lymph nodes, bone marrow, and central nervous system.^1,2,4 Patients with multiple tumors on the leg have a particularly poor prognosis; in particular, having 1 or more lesions on the leg results in a 43% 3-year survival rate while having multiple lesions has a 36% 3-year survival rate compared with a 77% 3-year survival rate for patients with the non–leg subtype or a single lesion.3 Treatment with rituximab has been shown to be effective in at least short-term control of the disease, and the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is the standard of treatment.^3,4

Primary cutaneous diffuse large B-cell lymphoma, leg type, can mimic multiple other cutaneous presentations of disease. Myeloid sarcoma (leukemia cutis) is a rare condition that presents as an extramedullary tumor often simultaneously with the onset or relapse of acute myeloid leukemia.⁵ Our patient had no history of leukemia, but myeloid sarcoma may predate acute myeloid leukemia in about a quarter of cases.⁵ It most commonly presents histologically as a diffuse dermal infiltrate that splays between collagen bundles and often is associated with an overlying Grenz zone. A nodular, or perivascular and periadnexal, pattern also may be seen. Upon closer inspection, the infiltrate is composed of immature myeloid cells (blasts) with background inflammation occasionally containing eosinophils. The immunohistochemical profile varies depending on the type of differentiation and degree of maturity of the cells. The histologic findings in our patient were inconsistent with myeloid sarcoma.

Erythema elevatum diutinum (EED) usually presents as dark red, brown, or violaceous papules or plaques and often is found on the extensor surfaces. It often is associated with hematologic abnormalities as well as recurrent bacterial or viral infections.⁶ Histologically, EED initially manifests as leukocytoclastic vasculitis with a mixed inflammatory infiltrate typically featuring an abundance of neutrophils, making this condition unlikely in this case. As the lesion progresses, fibrosis and scarring ensue as inflammation wanes. The fibrosis often is described as having an onion skin–like pattern, which is characteristic of established EED lesions. Our patient had no history of vasculitis, and the histologic findings were inconsistent with EED.

Angiosarcoma can present as a central nodule surrounded by an erythematous plaque. Although potentially clinically similar to primary cutaneous diffuse large B-cell lymphoma, leg type, angiosarcoma was unlikely in this case because of an absence of lymphedema and no history of radiation to the leg, both of which are key historical features of angiosarcoma.⁷ Additionally, the histology of cutaneous angiosarcoma is marked by vascular proliferation, which was not seen in the lesion biopsied in our patient. The histology of angiosarcoma is that of an atypical vascular proliferation, and a hallmark feature is infiltration between collagen, often referred to as giving the appearance of dissection between collagen bundles. The degree of atypia can vary widely, and epithelioid variants exist, producing a potential diagnostic pitfall. Lesional cells are positive for vascular markers, which can be used for confirmation of the endothelial lineage.

Sarcoidosis is notorious for its mimicry, which can be the case both clinically and histologically. Characteristic pathology of sarcoidosis is that of well-formed epithelioid granulomas with minimal associated inflammation and lack of caseating necrosis. Our patient had no known history of systemic sarcoidosis, and the pathologic features of noncaseating granulomas were not present. As a diagnosis of exclusion, correlation with special stains and culture studies is necessary to exclude an infectious process. The differential diagnosis for sarcoidal granulomatous dermatitis also includes foreign body reaction, inflammatory bowel disease, and granulomatous cheilitis, among others.

The Diagnosis: Cutaneous B-cell Lymphoma

Shave biopsies of 3 lesions revealed a dense, diffuse, atypical lymphoid infiltrate occupying the entirety of the dermis and obscuring the dermoepidermal junction. The infiltrate consisted predominantly of largesized lymphoid cells with fine chromatin and conspicuous nucleoli (Figure). Immunohistochemistry was positive for CD45 and CD20, indicating B-cell lineage. Bcl-2, multiple myeloma oncogene 1, and forkhead box protein P1 also were expressed in the vast majority of lesional cells, distinguishing the lesion from other forms of cutaneous B-cell lymphomas.¹ These findings were consistent with large B-cell lymphoma with a high proliferation index, consistent with primary cutaneous diffuse large B-cell lymphoma, leg type, which often presents on the lower leg.² The patient had a negative systemic workup including bone marrow biopsy. He was started on the R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) chemotherapy regimen.

Primary cutaneous diffuse large B-cell lymphoma, leg type, is an intermediately aggressive and rare form of B-cell lymphoma with a poor prognosis that primarily affects elderly female patients. Primary cutaneous diffuse large B-cell lymphoma, leg type, accounts for only 1% to 3% of cutaneous lymphomas and approximately 10% to 20% of primary cutaneous B-cell lymphomas.² It typically presents as multiple red-brown or bluish nodules on the lower extremities or trunk. Presentation as a solitary nodule also is possible.^1,2 Histologic analysis of primary cutaneous diffuse large B-cell lymphoma, leg type, reveals large cells with round nuclei (immunoblasts and centroblasts), and the immunohistochemical profile shows strong Bcl-2 expression often accompanied by the multiple myeloma oncogene 1 protein.³ The 5-year survival rate is approximately 50%, which is lower than other types of primary cutaneous B-cell lymphomas, and the progression of disease is characterized by frequent relapses and involvement of extracutaneous regions such as the lymph nodes, bone marrow, and central nervous system.^1,2,4 Patients with multiple tumors on the leg have a particularly poor prognosis; in particular, having 1 or more lesions on the leg results in a 43% 3-year survival rate while having multiple lesions has a 36% 3-year survival rate compared with a 77% 3-year survival rate for patients with the non–leg subtype or a single lesion.3 Treatment with rituximab has been shown to be effective in at least short-term control of the disease, and the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is the standard of treatment.^3,4

Primary cutaneous diffuse large B-cell lymphoma, leg type, can mimic multiple other cutaneous presentations of disease. Myeloid sarcoma (leukemia cutis) is a rare condition that presents as an extramedullary tumor often simultaneously with the onset or relapse of acute myeloid leukemia.⁵ Our patient had no history of leukemia, but myeloid sarcoma may predate acute myeloid leukemia in about a quarter of cases.⁵ It most commonly presents histologically as a diffuse dermal infiltrate that splays between collagen bundles and often is associated with an overlying Grenz zone. A nodular, or perivascular and periadnexal, pattern also may be seen. Upon closer inspection, the infiltrate is composed of immature myeloid cells (blasts) with background inflammation occasionally containing eosinophils. The immunohistochemical profile varies depending on the type of differentiation and degree of maturity of the cells. The histologic findings in our patient were inconsistent with myeloid sarcoma.

Erythema elevatum diutinum (EED) usually presents as dark red, brown, or violaceous papules or plaques and often is found on the extensor surfaces. It often is associated with hematologic abnormalities as well as recurrent bacterial or viral infections.⁶ Histologically, EED initially manifests as leukocytoclastic vasculitis with a mixed inflammatory infiltrate typically featuring an abundance of neutrophils, making this condition unlikely in this case. As the lesion progresses, fibrosis and scarring ensue as inflammation wanes. The fibrosis often is described as having an onion skin–like pattern, which is characteristic of established EED lesions. Our patient had no history of vasculitis, and the histologic findings were inconsistent with EED.

Angiosarcoma can present as a central nodule surrounded by an erythematous plaque. Although potentially clinically similar to primary cutaneous diffuse large B-cell lymphoma, leg type, angiosarcoma was unlikely in this case because of an absence of lymphedema and no history of radiation to the leg, both of which are key historical features of angiosarcoma.⁷ Additionally, the histology of cutaneous angiosarcoma is marked by vascular proliferation, which was not seen in the lesion biopsied in our patient. The histology of angiosarcoma is that of an atypical vascular proliferation, and a hallmark feature is infiltration between collagen, often referred to as giving the appearance of dissection between collagen bundles. The degree of atypia can vary widely, and epithelioid variants exist, producing a potential diagnostic pitfall. Lesional cells are positive for vascular markers, which can be used for confirmation of the endothelial lineage.

Sarcoidosis is notorious for its mimicry, which can be the case both clinically and histologically. Characteristic pathology of sarcoidosis is that of well-formed epithelioid granulomas with minimal associated inflammation and lack of caseating necrosis. Our patient had no known history of systemic sarcoidosis, and the pathologic features of noncaseating granulomas were not present. As a diagnosis of exclusion, correlation with special stains and culture studies is necessary to exclude an infectious process. The differential diagnosis for sarcoidal granulomatous dermatitis also includes foreign body reaction, inflammatory bowel disease, and granulomatous cheilitis, among others.

The Diagnosis: Cutaneous B-cell Lymphoma

Shave biopsies of 3 lesions revealed a dense, diffuse, atypical lymphoid infiltrate occupying the entirety of the dermis and obscuring the dermoepidermal junction. The infiltrate consisted predominantly of largesized lymphoid cells with fine chromatin and conspicuous nucleoli (Figure). Immunohistochemistry was positive for CD45 and CD20, indicating B-cell lineage. Bcl-2, multiple myeloma oncogene 1, and forkhead box protein P1 also were expressed in the vast majority of lesional cells, distinguishing the lesion from other forms of cutaneous B-cell lymphomas.¹ These findings were consistent with large B-cell lymphoma with a high proliferation index, consistent with primary cutaneous diffuse large B-cell lymphoma, leg type, which often presents on the lower leg.² The patient had a negative systemic workup including bone marrow biopsy. He was started on the R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) chemotherapy regimen.

Primary cutaneous diffuse large B-cell lymphoma, leg type, is an intermediately aggressive and rare form of B-cell lymphoma with a poor prognosis that primarily affects elderly female patients. Primary cutaneous diffuse large B-cell lymphoma, leg type, accounts for only 1% to 3% of cutaneous lymphomas and approximately 10% to 20% of primary cutaneous B-cell lymphomas.² It typically presents as multiple red-brown or bluish nodules on the lower extremities or trunk. Presentation as a solitary nodule also is possible.^1,2 Histologic analysis of primary cutaneous diffuse large B-cell lymphoma, leg type, reveals large cells with round nuclei (immunoblasts and centroblasts), and the immunohistochemical profile shows strong Bcl-2 expression often accompanied by the multiple myeloma oncogene 1 protein.³ The 5-year survival rate is approximately 50%, which is lower than other types of primary cutaneous B-cell lymphomas, and the progression of disease is characterized by frequent relapses and involvement of extracutaneous regions such as the lymph nodes, bone marrow, and central nervous system.^1,2,4 Patients with multiple tumors on the leg have a particularly poor prognosis; in particular, having 1 or more lesions on the leg results in a 43% 3-year survival rate while having multiple lesions has a 36% 3-year survival rate compared with a 77% 3-year survival rate for patients with the non–leg subtype or a single lesion.3 Treatment with rituximab has been shown to be effective in at least short-term control of the disease, and the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is the standard of treatment.^3,4

Primary cutaneous diffuse large B-cell lymphoma, leg type, can mimic multiple other cutaneous presentations of disease. Myeloid sarcoma (leukemia cutis) is a rare condition that presents as an extramedullary tumor often simultaneously with the onset or relapse of acute myeloid leukemia.⁵ Our patient had no history of leukemia, but myeloid sarcoma may predate acute myeloid leukemia in about a quarter of cases.⁵ It most commonly presents histologically as a diffuse dermal infiltrate that splays between collagen bundles and often is associated with an overlying Grenz zone. A nodular, or perivascular and periadnexal, pattern also may be seen. Upon closer inspection, the infiltrate is composed of immature myeloid cells (blasts) with background inflammation occasionally containing eosinophils. The immunohistochemical profile varies depending on the type of differentiation and degree of maturity of the cells. The histologic findings in our patient were inconsistent with myeloid sarcoma.

Erythema elevatum diutinum (EED) usually presents as dark red, brown, or violaceous papules or plaques and often is found on the extensor surfaces. It often is associated with hematologic abnormalities as well as recurrent bacterial or viral infections.⁶ Histologically, EED initially manifests as leukocytoclastic vasculitis with a mixed inflammatory infiltrate typically featuring an abundance of neutrophils, making this condition unlikely in this case. As the lesion progresses, fibrosis and scarring ensue as inflammation wanes. The fibrosis often is described as having an onion skin–like pattern, which is characteristic of established EED lesions. Our patient had no history of vasculitis, and the histologic findings were inconsistent with EED.

Angiosarcoma can present as a central nodule surrounded by an erythematous plaque. Although potentially clinically similar to primary cutaneous diffuse large B-cell lymphoma, leg type, angiosarcoma was unlikely in this case because of an absence of lymphedema and no history of radiation to the leg, both of which are key historical features of angiosarcoma.⁷ Additionally, the histology of cutaneous angiosarcoma is marked by vascular proliferation, which was not seen in the lesion biopsied in our patient. The histology of angiosarcoma is that of an atypical vascular proliferation, and a hallmark feature is infiltration between collagen, often referred to as giving the appearance of dissection between collagen bundles. The degree of atypia can vary widely, and epithelioid variants exist, producing a potential diagnostic pitfall. Lesional cells are positive for vascular markers, which can be used for confirmation of the endothelial lineage.

Sarcoidosis is notorious for its mimicry, which can be the case both clinically and histologically. Characteristic pathology of sarcoidosis is that of well-formed epithelioid granulomas with minimal associated inflammation and lack of caseating necrosis. Our patient had no known history of systemic sarcoidosis, and the pathologic features of noncaseating granulomas were not present. As a diagnosis of exclusion, correlation with special stains and culture studies is necessary to exclude an infectious process. The differential diagnosis for sarcoidal granulomatous dermatitis also includes foreign body reaction, inflammatory bowel disease, and granulomatous cheilitis, among others.

The Diagnosis: Reactive Perforating Collagenosis

Reactive perforating collagenosis (RPC) may be either acquired or inherited. It is 1 of 4 classical forms of transepithelial elimination, which also includes elastosis perforans serpiginosa (EPS) as well as perforating folliculitis and Kyrle disease. These 4 forms of transepithelial elimination share characteristics of the elimination of altered dermal components through the epidermis.¹ The acquired subtype of RPC frequently occurs in patients with diabetes mellitus and end-stage renal disease,² both present in our patient.

Clinical presentation typically shows pruritic hyperkeratotic papules with a central crater filled with crust that frequently are distributed on the extensor surfaces of the extremities, often in a linear pattern.³ The perforating papules and nodules occasionally may involve the trunk and face.⁴ Histopathologic examination is characterized by the elimination of altered collagen through the epidermis. Established lesions may show a cup-shaped depression of the epidermis filled with a keratin plug. The underlying dermis will show vertically oriented basophilic collagen fibers with focal extrusion through the epidermis, and elastic fibers will be absent.⁵ The exact pathophysiology of this disease is unknown, but it may represent a cutaneous response to superficial trauma caused by intense scratching.⁶

Standard treatment protocols are not well established for this condition, but some evidence shows that a combination of treatments can help ameliorate symptoms, even if they are not curative.⁷ Treatments without strong evidence have included a wide range of topical, systemic, and other therapies. Case series and anecdotal reports have used retinoids, corticosteroids, menthol, antibiotics, allopurinol antihistamines, cryotherapy, and lasers.⁸ One case was treated with a combination of narrowband UVB phototherapy and doxycycline with resolution in approximately 6 weeks.⁹ Other cases have been cured using triple therapy with antihistamines, topical or injected steroids, and emollients or oral antibiotics.⁷ Evidence shows that there may be benefit to combining multiple different treatment types that target pruritus, inflammation, and collagen damage.^7,9 This disease usually cannot be cured, but it may be improved by the available treatments.

The differential diagnosis includes delusional parasitosis, EPS, perforating folliculitis, and prurigo nodularis. Delusional parasitosis also can be characterized by excoriated plaques and a sensation of parasites infesting the skin, as our patient described.¹⁰ However, it can be differentiated from RPC by the fact that it is a diagnosis of exclusion, which would not have the histopathologic findings of the elimination of collagen from the epidermis, as was demonstrated in our patient.¹¹ Elastosis perforans serpiginosa is in the same family of perforating diseases as RPC; however, EPS typically appears in children or young adults and often is associated with other genetic disorders. Physical examination in a patient with EPS would reveal keratotic papules in a serpiginous pattern, whereas our patient had discrete lesions without any serpiginous pattern. The histopathologic appearance of EPS would reveal plugs of elastic fibers rather than collagen fibers, as was demonstrated in our patient.⁸ Perforating folliculitis, while also demonstrating transepithelial elimination similar to RPC, would appear as erythematous follicular papules with small central keratotic plugs and histopathologic findings of a widely dilated follicle with a mass of keratotic debris.¹² Prurigo nodularis would appear as dome-shaped papulonodules with varying degrees of scale, crust, and erosion, with a histopathologic appearance of hyperplasia and thick hyperkeratosis.¹¹

Overall, the histopathology is paramount in differentiating RPC from the alternative diagnoses, with the extrusion of collagen from the epidermis not being seen in these other conditions. The coupling of the medical history (type 2 diabetes mellitus and end-stage renal disease) with the clinical presentation and skin biopsy findings confirmed the diagnosis of RPC.

The Diagnosis: Reactive Perforating Collagenosis

Reactive perforating collagenosis (RPC) may be either acquired or inherited. It is 1 of 4 classical forms of transepithelial elimination, which also includes elastosis perforans serpiginosa (EPS) as well as perforating folliculitis and Kyrle disease. These 4 forms of transepithelial elimination share characteristics of the elimination of altered dermal components through the epidermis.¹ The acquired subtype of RPC frequently occurs in patients with diabetes mellitus and end-stage renal disease,² both present in our patient.

Clinical presentation typically shows pruritic hyperkeratotic papules with a central crater filled with crust that frequently are distributed on the extensor surfaces of the extremities, often in a linear pattern.³ The perforating papules and nodules occasionally may involve the trunk and face.⁴ Histopathologic examination is characterized by the elimination of altered collagen through the epidermis. Established lesions may show a cup-shaped depression of the epidermis filled with a keratin plug. The underlying dermis will show vertically oriented basophilic collagen fibers with focal extrusion through the epidermis, and elastic fibers will be absent.⁵ The exact pathophysiology of this disease is unknown, but it may represent a cutaneous response to superficial trauma caused by intense scratching.⁶

Standard treatment protocols are not well established for this condition, but some evidence shows that a combination of treatments can help ameliorate symptoms, even if they are not curative.⁷ Treatments without strong evidence have included a wide range of topical, systemic, and other therapies. Case series and anecdotal reports have used retinoids, corticosteroids, menthol, antibiotics, allopurinol antihistamines, cryotherapy, and lasers.⁸ One case was treated with a combination of narrowband UVB phototherapy and doxycycline with resolution in approximately 6 weeks.⁹ Other cases have been cured using triple therapy with antihistamines, topical or injected steroids, and emollients or oral antibiotics.⁷ Evidence shows that there may be benefit to combining multiple different treatment types that target pruritus, inflammation, and collagen damage.^7,9 This disease usually cannot be cured, but it may be improved by the available treatments.

The differential diagnosis includes delusional parasitosis, EPS, perforating folliculitis, and prurigo nodularis. Delusional parasitosis also can be characterized by excoriated plaques and a sensation of parasites infesting the skin, as our patient described.¹⁰ However, it can be differentiated from RPC by the fact that it is a diagnosis of exclusion, which would not have the histopathologic findings of the elimination of collagen from the epidermis, as was demonstrated in our patient.¹¹ Elastosis perforans serpiginosa is in the same family of perforating diseases as RPC; however, EPS typically appears in children or young adults and often is associated with other genetic disorders. Physical examination in a patient with EPS would reveal keratotic papules in a serpiginous pattern, whereas our patient had discrete lesions without any serpiginous pattern. The histopathologic appearance of EPS would reveal plugs of elastic fibers rather than collagen fibers, as was demonstrated in our patient.⁸ Perforating folliculitis, while also demonstrating transepithelial elimination similar to RPC, would appear as erythematous follicular papules with small central keratotic plugs and histopathologic findings of a widely dilated follicle with a mass of keratotic debris.¹² Prurigo nodularis would appear as dome-shaped papulonodules with varying degrees of scale, crust, and erosion, with a histopathologic appearance of hyperplasia and thick hyperkeratosis.¹¹

Overall, the histopathology is paramount in differentiating RPC from the alternative diagnoses, with the extrusion of collagen from the epidermis not being seen in these other conditions. The coupling of the medical history (type 2 diabetes mellitus and end-stage renal disease) with the clinical presentation and skin biopsy findings confirmed the diagnosis of RPC.

The Diagnosis: Reactive Perforating Collagenosis

Reactive perforating collagenosis (RPC) may be either acquired or inherited. It is 1 of 4 classical forms of transepithelial elimination, which also includes elastosis perforans serpiginosa (EPS) as well as perforating folliculitis and Kyrle disease. These 4 forms of transepithelial elimination share characteristics of the elimination of altered dermal components through the epidermis.¹ The acquired subtype of RPC frequently occurs in patients with diabetes mellitus and end-stage renal disease,² both present in our patient.

Clinical presentation typically shows pruritic hyperkeratotic papules with a central crater filled with crust that frequently are distributed on the extensor surfaces of the extremities, often in a linear pattern.³ The perforating papules and nodules occasionally may involve the trunk and face.⁴ Histopathologic examination is characterized by the elimination of altered collagen through the epidermis. Established lesions may show a cup-shaped depression of the epidermis filled with a keratin plug. The underlying dermis will show vertically oriented basophilic collagen fibers with focal extrusion through the epidermis, and elastic fibers will be absent.⁵ The exact pathophysiology of this disease is unknown, but it may represent a cutaneous response to superficial trauma caused by intense scratching.⁶

Standard treatment protocols are not well established for this condition, but some evidence shows that a combination of treatments can help ameliorate symptoms, even if they are not curative.⁷ Treatments without strong evidence have included a wide range of topical, systemic, and other therapies. Case series and anecdotal reports have used retinoids, corticosteroids, menthol, antibiotics, allopurinol antihistamines, cryotherapy, and lasers.⁸ One case was treated with a combination of narrowband UVB phototherapy and doxycycline with resolution in approximately 6 weeks.⁹ Other cases have been cured using triple therapy with antihistamines, topical or injected steroids, and emollients or oral antibiotics.⁷ Evidence shows that there may be benefit to combining multiple different treatment types that target pruritus, inflammation, and collagen damage.^7,9 This disease usually cannot be cured, but it may be improved by the available treatments.

The differential diagnosis includes delusional parasitosis, EPS, perforating folliculitis, and prurigo nodularis. Delusional parasitosis also can be characterized by excoriated plaques and a sensation of parasites infesting the skin, as our patient described.¹⁰ However, it can be differentiated from RPC by the fact that it is a diagnosis of exclusion, which would not have the histopathologic findings of the elimination of collagen from the epidermis, as was demonstrated in our patient.¹¹ Elastosis perforans serpiginosa is in the same family of perforating diseases as RPC; however, EPS typically appears in children or young adults and often is associated with other genetic disorders. Physical examination in a patient with EPS would reveal keratotic papules in a serpiginous pattern, whereas our patient had discrete lesions without any serpiginous pattern. The histopathologic appearance of EPS would reveal plugs of elastic fibers rather than collagen fibers, as was demonstrated in our patient.⁸ Perforating folliculitis, while also demonstrating transepithelial elimination similar to RPC, would appear as erythematous follicular papules with small central keratotic plugs and histopathologic findings of a widely dilated follicle with a mass of keratotic debris.¹² Prurigo nodularis would appear as dome-shaped papulonodules with varying degrees of scale, crust, and erosion, with a histopathologic appearance of hyperplasia and thick hyperkeratosis.¹¹

Overall, the histopathology is paramount in differentiating RPC from the alternative diagnoses, with the extrusion of collagen from the epidermis not being seen in these other conditions. The coupling of the medical history (type 2 diabetes mellitus and end-stage renal disease) with the clinical presentation and skin biopsy findings confirmed the diagnosis of RPC.