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Acute Tender Papules on the Arms and Legs
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Benjamin Freemyer, MD
Steven Mays, MD
Ronald Rapini, MD

The Diagnosis: Erythema Nodosum Leprosum

Erythema nodosum leprosum (ENL) is a type 2 reaction sometimes seen in patients infected with Mycobacterium leprae—primarily those with lepromatous or borderline lepromatous subtypes. Clinically, ENL manifests with abrupt onset of tender erythematous papules with associated fevers and general malaise. Studies have demonstrated a complex immune system reaction in ENL, but the detailed pathophysiology is not fully understood.1 Biopsies conducted within 24 hours of lesion formation are most elucidating. Foamy histiocytes admixed with neutrophils are seen in the subcutis, often causing a lobular panniculitis (quiz image).2 Neutrophils rarely are seen in other types of leprosy and thus are a useful diagnostic clue for ENL. Vasculitis of small- to medium-sized vessels can be seen but is not a necessary diagnostic criterion. Fite staining will highlight many acid-fast bacilli within the histiocytes (Figure 1).

FIGURE 1. Erythema nodosum leprosum. Fite staining highlights numerous intracellular acid-fast bacilli (original magnification ×400).

Erythema nodosum leprosum is treated with a combination of immunosuppressants such as prednisone and thalidomide. Our patient was taking triple-antibiotic therapy—dapsone, rifampin, and clofazimine—for lepromatous leprosy when the erythematous papules developed on the arms and legs. After a skin biopsy confirmed the diagnosis of ENL, he was started on prednisone 20 mg daily with plans for close follow-up. Unfortunately, the patient was subsequently lost to follow-up.

Acute febrile neutrophilic dermatosis (also known as Sweet syndrome) is an acute inflammatory disease characterized by abrupt onset of painful erythematous papules, plaques, or nodules on the skin. It often is seen in association with preceding infections (especially those in the upper respiratory or gastrointestinal tracts), hematologic malignancies, inflammatory bowel disease, or exposure to certain classes of medications (eg, granulocyte colony-stimulating factor, tyrosine kinase inhibitors, various antibiotics).3 Histologically, acute febrile neutrophilic dermatosis is characterized by dense neutrophilic infiltrates, often with notable dermal edema (Figure 2).4 Many cases also show leukocytoclastic vasculitis; however, foamy histiocytes are not a notable component of the inflammatory infiltrate, though a histiocytoid form of acute febrile neutrophilic dermatosis has been described.5 Infections must be rigorously ruled out prior to diagnosing a patient with acute febrile neutrophilic dermatosis, making it a diagnosis of exclusion.

FIGURE 2. Acute febrile neutrophilic dermatosis. Dense neutrophilic infiltrates with brisk papillary dermal edema are present (H&E, original magnification ×100).

Cutaneous coccidioidomycosis is an infection caused by the dimorphic fungi Coccidioides immitis or Coccidioides posadasii. Cutaneous disease is rare but can occur from direct inoculation or dissemination from pulmonary disease in immunocompetent or immunocompromised patients. Papules, pustules, or plaques are seen clinically. Histologically, cutaneous coccidioidomycosis shows spherules that vary from 10 to 100 μm and are filled with multiple smaller endospores (Figure 3).6 Pseudoepitheliomatous hyperplasia with dense suppurative and granulomatous infiltrates also is seen.

FIGURE 3. Cutaneous coccidioidomycosis. Classic intracytoplasmic spherules are present (H&E, original magnification ×400).

Erythema induratum is characterized by tender nodules on the lower extremities and has a substantial female predominance. Many cases are associated with Mycobacterium tuberculosis infection. The bacteria are not seen directly in the skin but are instead detectable through DNA polymerase chain reaction testing or investigation of other organ systems.7,8 Histologically, lesions show a lobular panniculitis with a mixed infiltrate. Vasculitis is seen in approximately 90% of erythema induratum cases vs approximately 25% of classic ENL cases (Figure 4),2,9 which has led some to use the term nodular vasculitis to describe this disease entity. Nodular vasculitis is considered by others to be a distinct disease entity in which there are clinical and histologic features similar to erythema induratum but no evidence of M tuberculosis infection.9

FIGURE 4. Erythema induratum. Lobular panniculitis with vasculitis of a small-caliber vessel is present (H&E, original magnification ×100).

Polyarteritis nodosa is a vasculitis that affects medium- sized vessels of various organ systems. The presenting signs and symptoms vary based on the affected organ systems. Palpable to retiform purpura, livedo racemosa, subcutaneous nodules, or ulcers are seen when the skin is involved. The histologic hallmark is necrotizing vasculitis of medium-sized arterioles (Figure 5), although leukocytoclastic vasculitis of small-caliber vessels also can be seen in biopsies of affected skin.10 The vascular changes are said to be segmental, with uninvolved segments interspersed with involved segments. Antineutrophil cytoplasmic antibody (ANCA)– associated vasculitis also must be considered when one sees leukocytoclastic vasculitis of small-caliber vessels in the skin, as it can be distinguished most readily by detecting circulating antibodies specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA).

FIGURE 5. Polyarteritis nodosa. Neutrophils and karyorrhectic debris surround a medium-caliber vessel (H&E, original magnification ×40).

References
  1. Polycarpou A, Walker SL, Lockwood DNJ. A systematic review of immunological studies of erythema nodosum leprosum. Front Immunol. 2017;8:233. doi:10.3389/fimmu.2017.00233
  2. Massone C, Belachew WA, Schettini A. Histopathology of the lepromatous skin biopsy. Clin Dermatol. 2015;33:38-45. doi:10.1016/j.clindermatol.2014.10.003
  3. Cohen PR. Sweet’s syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:1-28. doi:10.1186/1750-1172-2-34
  4. Ratzinger G, Burgdorf W, Zelger BG, et al. Acute febrile neutrophilic dermatosis: a histopathologic study of 31 cases with review of literature. Am J Dermatopathol. 2007;29:125-133. doi:10.1097/01.dad.0000249887.59810.76
  5. Wilson TC, Stone MS, Swick BL. Histiocytoid Sweet syndrome with haloed myeloid cells masquerading as a cryptococcal infection. Am J Dermatopathology. 2014;36:264-269. doi:10.1097/DAD.0b013e31828b811b
  6. Guarner J, Brandt ME. Histopathologic diagnosis of fungal infections in the 21st century. Clin Microbiol Rev. 2011;24:247-280. doi:10.1128/CMR.00053-10
  7. Schneider JW, Jordaan HF, Geiger DH, et al. Erythema induratum of Bazin: a clinicopathological study of 20 cases of Mycobacterium tuberculosis DNA in skin lesions by polymerase chain reaction. Am J Dermatopathol. 1995;17:350-356. doi:10.1097/00000372-199508000-00008
  8. Boonchai W, Suthipinittharm P, Mahaisavariya P. Panniculitis in tuberculosis: a clinicopathologic study of nodular panniculitis associated with tuberculosis. Int J Dermatol. 1998;37:361-363. doi:10.1046/j.1365-4362.1998.00299.x
  9. Segura S, Pujol RM, Trindade F, et al. Vasculitis in erythema induratum of Bazin: a histopathologic study of 101 biopsy specimens from 86 patients. J Am Acad Dermatol. 2008;59:839-851. doi:10.1016/j.jaad.2008.07.030
  10. Ishiguro N, Kawashima M. Cutaneous polyarteritis nodosa: a report of 16 cases with clinical and histopathological analysis and a review of the published work. J Dermatol. 2010;37:85-93. doi:10.1111/j.1346-8138.2009.00752.x
Author and Disclosure Information

From the Department of Dermatology, University of Texas Health Science Center at Houston.

The authors have no relevant financial disclosures to report.

Correspondence: Benjamin Freemyer, MD, 6500 W Loop S, Ste 200-A, Houston, TX 77401 (benjamin.freemyer@uth.tmc.edu).

Cutis. 2024 September;114(3):87, 93-94. doi:10.12788/cutis.1088

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Author(s)
Benjamin Freemyer, MD
Steven Mays, MD
Ronald Rapini, MD
Author(s)
Benjamin Freemyer, MD
Steven Mays, MD
Ronald Rapini, MD
Author and Disclosure Information

From the Department of Dermatology, University of Texas Health Science Center at Houston.

The authors have no relevant financial disclosures to report.

Correspondence: Benjamin Freemyer, MD, 6500 W Loop S, Ste 200-A, Houston, TX 77401 (benjamin.freemyer@uth.tmc.edu).

Cutis. 2024 September;114(3):87, 93-94. doi:10.12788/cutis.1088

Author and Disclosure Information

From the Department of Dermatology, University of Texas Health Science Center at Houston.

The authors have no relevant financial disclosures to report.

Correspondence: Benjamin Freemyer, MD, 6500 W Loop S, Ste 200-A, Houston, TX 77401 (benjamin.freemyer@uth.tmc.edu).

Cutis. 2024 September;114(3):87, 93-94. doi:10.12788/cutis.1088

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The Diagnosis: Erythema Nodosum Leprosum

Erythema nodosum leprosum (ENL) is a type 2 reaction sometimes seen in patients infected with Mycobacterium leprae—primarily those with lepromatous or borderline lepromatous subtypes. Clinically, ENL manifests with abrupt onset of tender erythematous papules with associated fevers and general malaise. Studies have demonstrated a complex immune system reaction in ENL, but the detailed pathophysiology is not fully understood.1 Biopsies conducted within 24 hours of lesion formation are most elucidating. Foamy histiocytes admixed with neutrophils are seen in the subcutis, often causing a lobular panniculitis (quiz image).2 Neutrophils rarely are seen in other types of leprosy and thus are a useful diagnostic clue for ENL. Vasculitis of small- to medium-sized vessels can be seen but is not a necessary diagnostic criterion. Fite staining will highlight many acid-fast bacilli within the histiocytes (Figure 1).

FIGURE 1. Erythema nodosum leprosum. Fite staining highlights numerous intracellular acid-fast bacilli (original magnification ×400).

Erythema nodosum leprosum is treated with a combination of immunosuppressants such as prednisone and thalidomide. Our patient was taking triple-antibiotic therapy—dapsone, rifampin, and clofazimine—for lepromatous leprosy when the erythematous papules developed on the arms and legs. After a skin biopsy confirmed the diagnosis of ENL, he was started on prednisone 20 mg daily with plans for close follow-up. Unfortunately, the patient was subsequently lost to follow-up.

Acute febrile neutrophilic dermatosis (also known as Sweet syndrome) is an acute inflammatory disease characterized by abrupt onset of painful erythematous papules, plaques, or nodules on the skin. It often is seen in association with preceding infections (especially those in the upper respiratory or gastrointestinal tracts), hematologic malignancies, inflammatory bowel disease, or exposure to certain classes of medications (eg, granulocyte colony-stimulating factor, tyrosine kinase inhibitors, various antibiotics).3 Histologically, acute febrile neutrophilic dermatosis is characterized by dense neutrophilic infiltrates, often with notable dermal edema (Figure 2).4 Many cases also show leukocytoclastic vasculitis; however, foamy histiocytes are not a notable component of the inflammatory infiltrate, though a histiocytoid form of acute febrile neutrophilic dermatosis has been described.5 Infections must be rigorously ruled out prior to diagnosing a patient with acute febrile neutrophilic dermatosis, making it a diagnosis of exclusion.

FIGURE 2. Acute febrile neutrophilic dermatosis. Dense neutrophilic infiltrates with brisk papillary dermal edema are present (H&E, original magnification ×100).

Cutaneous coccidioidomycosis is an infection caused by the dimorphic fungi Coccidioides immitis or Coccidioides posadasii. Cutaneous disease is rare but can occur from direct inoculation or dissemination from pulmonary disease in immunocompetent or immunocompromised patients. Papules, pustules, or plaques are seen clinically. Histologically, cutaneous coccidioidomycosis shows spherules that vary from 10 to 100 μm and are filled with multiple smaller endospores (Figure 3).6 Pseudoepitheliomatous hyperplasia with dense suppurative and granulomatous infiltrates also is seen.

FIGURE 3. Cutaneous coccidioidomycosis. Classic intracytoplasmic spherules are present (H&E, original magnification ×400).

Erythema induratum is characterized by tender nodules on the lower extremities and has a substantial female predominance. Many cases are associated with Mycobacterium tuberculosis infection. The bacteria are not seen directly in the skin but are instead detectable through DNA polymerase chain reaction testing or investigation of other organ systems.7,8 Histologically, lesions show a lobular panniculitis with a mixed infiltrate. Vasculitis is seen in approximately 90% of erythema induratum cases vs approximately 25% of classic ENL cases (Figure 4),2,9 which has led some to use the term nodular vasculitis to describe this disease entity. Nodular vasculitis is considered by others to be a distinct disease entity in which there are clinical and histologic features similar to erythema induratum but no evidence of M tuberculosis infection.9

FIGURE 4. Erythema induratum. Lobular panniculitis with vasculitis of a small-caliber vessel is present (H&E, original magnification ×100).

Polyarteritis nodosa is a vasculitis that affects medium- sized vessels of various organ systems. The presenting signs and symptoms vary based on the affected organ systems. Palpable to retiform purpura, livedo racemosa, subcutaneous nodules, or ulcers are seen when the skin is involved. The histologic hallmark is necrotizing vasculitis of medium-sized arterioles (Figure 5), although leukocytoclastic vasculitis of small-caliber vessels also can be seen in biopsies of affected skin.10 The vascular changes are said to be segmental, with uninvolved segments interspersed with involved segments. Antineutrophil cytoplasmic antibody (ANCA)– associated vasculitis also must be considered when one sees leukocytoclastic vasculitis of small-caliber vessels in the skin, as it can be distinguished most readily by detecting circulating antibodies specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA).

FIGURE 5. Polyarteritis nodosa. Neutrophils and karyorrhectic debris surround a medium-caliber vessel (H&E, original magnification ×40).

The Diagnosis: Erythema Nodosum Leprosum

Erythema nodosum leprosum (ENL) is a type 2 reaction sometimes seen in patients infected with Mycobacterium leprae—primarily those with lepromatous or borderline lepromatous subtypes. Clinically, ENL manifests with abrupt onset of tender erythematous papules with associated fevers and general malaise. Studies have demonstrated a complex immune system reaction in ENL, but the detailed pathophysiology is not fully understood.1 Biopsies conducted within 24 hours of lesion formation are most elucidating. Foamy histiocytes admixed with neutrophils are seen in the subcutis, often causing a lobular panniculitis (quiz image).2 Neutrophils rarely are seen in other types of leprosy and thus are a useful diagnostic clue for ENL. Vasculitis of small- to medium-sized vessels can be seen but is not a necessary diagnostic criterion. Fite staining will highlight many acid-fast bacilli within the histiocytes (Figure 1).

FIGURE 1. Erythema nodosum leprosum. Fite staining highlights numerous intracellular acid-fast bacilli (original magnification ×400).

Erythema nodosum leprosum is treated with a combination of immunosuppressants such as prednisone and thalidomide. Our patient was taking triple-antibiotic therapy—dapsone, rifampin, and clofazimine—for lepromatous leprosy when the erythematous papules developed on the arms and legs. After a skin biopsy confirmed the diagnosis of ENL, he was started on prednisone 20 mg daily with plans for close follow-up. Unfortunately, the patient was subsequently lost to follow-up.

Acute febrile neutrophilic dermatosis (also known as Sweet syndrome) is an acute inflammatory disease characterized by abrupt onset of painful erythematous papules, plaques, or nodules on the skin. It often is seen in association with preceding infections (especially those in the upper respiratory or gastrointestinal tracts), hematologic malignancies, inflammatory bowel disease, or exposure to certain classes of medications (eg, granulocyte colony-stimulating factor, tyrosine kinase inhibitors, various antibiotics).3 Histologically, acute febrile neutrophilic dermatosis is characterized by dense neutrophilic infiltrates, often with notable dermal edema (Figure 2).4 Many cases also show leukocytoclastic vasculitis; however, foamy histiocytes are not a notable component of the inflammatory infiltrate, though a histiocytoid form of acute febrile neutrophilic dermatosis has been described.5 Infections must be rigorously ruled out prior to diagnosing a patient with acute febrile neutrophilic dermatosis, making it a diagnosis of exclusion.

FIGURE 2. Acute febrile neutrophilic dermatosis. Dense neutrophilic infiltrates with brisk papillary dermal edema are present (H&E, original magnification ×100).

Cutaneous coccidioidomycosis is an infection caused by the dimorphic fungi Coccidioides immitis or Coccidioides posadasii. Cutaneous disease is rare but can occur from direct inoculation or dissemination from pulmonary disease in immunocompetent or immunocompromised patients. Papules, pustules, or plaques are seen clinically. Histologically, cutaneous coccidioidomycosis shows spherules that vary from 10 to 100 μm and are filled with multiple smaller endospores (Figure 3).6 Pseudoepitheliomatous hyperplasia with dense suppurative and granulomatous infiltrates also is seen.

FIGURE 3. Cutaneous coccidioidomycosis. Classic intracytoplasmic spherules are present (H&E, original magnification ×400).

Erythema induratum is characterized by tender nodules on the lower extremities and has a substantial female predominance. Many cases are associated with Mycobacterium tuberculosis infection. The bacteria are not seen directly in the skin but are instead detectable through DNA polymerase chain reaction testing or investigation of other organ systems.7,8 Histologically, lesions show a lobular panniculitis with a mixed infiltrate. Vasculitis is seen in approximately 90% of erythema induratum cases vs approximately 25% of classic ENL cases (Figure 4),2,9 which has led some to use the term nodular vasculitis to describe this disease entity. Nodular vasculitis is considered by others to be a distinct disease entity in which there are clinical and histologic features similar to erythema induratum but no evidence of M tuberculosis infection.9

FIGURE 4. Erythema induratum. Lobular panniculitis with vasculitis of a small-caliber vessel is present (H&E, original magnification ×100).

Polyarteritis nodosa is a vasculitis that affects medium- sized vessels of various organ systems. The presenting signs and symptoms vary based on the affected organ systems. Palpable to retiform purpura, livedo racemosa, subcutaneous nodules, or ulcers are seen when the skin is involved. The histologic hallmark is necrotizing vasculitis of medium-sized arterioles (Figure 5), although leukocytoclastic vasculitis of small-caliber vessels also can be seen in biopsies of affected skin.10 The vascular changes are said to be segmental, with uninvolved segments interspersed with involved segments. Antineutrophil cytoplasmic antibody (ANCA)– associated vasculitis also must be considered when one sees leukocytoclastic vasculitis of small-caliber vessels in the skin, as it can be distinguished most readily by detecting circulating antibodies specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA).

FIGURE 5. Polyarteritis nodosa. Neutrophils and karyorrhectic debris surround a medium-caliber vessel (H&E, original magnification ×40).

References
  1. Polycarpou A, Walker SL, Lockwood DNJ. A systematic review of immunological studies of erythema nodosum leprosum. Front Immunol. 2017;8:233. doi:10.3389/fimmu.2017.00233
  2. Massone C, Belachew WA, Schettini A. Histopathology of the lepromatous skin biopsy. Clin Dermatol. 2015;33:38-45. doi:10.1016/j.clindermatol.2014.10.003
  3. Cohen PR. Sweet’s syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:1-28. doi:10.1186/1750-1172-2-34
  4. Ratzinger G, Burgdorf W, Zelger BG, et al. Acute febrile neutrophilic dermatosis: a histopathologic study of 31 cases with review of literature. Am J Dermatopathol. 2007;29:125-133. doi:10.1097/01.dad.0000249887.59810.76
  5. Wilson TC, Stone MS, Swick BL. Histiocytoid Sweet syndrome with haloed myeloid cells masquerading as a cryptococcal infection. Am J Dermatopathology. 2014;36:264-269. doi:10.1097/DAD.0b013e31828b811b
  6. Guarner J, Brandt ME. Histopathologic diagnosis of fungal infections in the 21st century. Clin Microbiol Rev. 2011;24:247-280. doi:10.1128/CMR.00053-10
  7. Schneider JW, Jordaan HF, Geiger DH, et al. Erythema induratum of Bazin: a clinicopathological study of 20 cases of Mycobacterium tuberculosis DNA in skin lesions by polymerase chain reaction. Am J Dermatopathol. 1995;17:350-356. doi:10.1097/00000372-199508000-00008
  8. Boonchai W, Suthipinittharm P, Mahaisavariya P. Panniculitis in tuberculosis: a clinicopathologic study of nodular panniculitis associated with tuberculosis. Int J Dermatol. 1998;37:361-363. doi:10.1046/j.1365-4362.1998.00299.x
  9. Segura S, Pujol RM, Trindade F, et al. Vasculitis in erythema induratum of Bazin: a histopathologic study of 101 biopsy specimens from 86 patients. J Am Acad Dermatol. 2008;59:839-851. doi:10.1016/j.jaad.2008.07.030
  10. Ishiguro N, Kawashima M. Cutaneous polyarteritis nodosa: a report of 16 cases with clinical and histopathological analysis and a review of the published work. J Dermatol. 2010;37:85-93. doi:10.1111/j.1346-8138.2009.00752.x
References
  1. Polycarpou A, Walker SL, Lockwood DNJ. A systematic review of immunological studies of erythema nodosum leprosum. Front Immunol. 2017;8:233. doi:10.3389/fimmu.2017.00233
  2. Massone C, Belachew WA, Schettini A. Histopathology of the lepromatous skin biopsy. Clin Dermatol. 2015;33:38-45. doi:10.1016/j.clindermatol.2014.10.003
  3. Cohen PR. Sweet’s syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:1-28. doi:10.1186/1750-1172-2-34
  4. Ratzinger G, Burgdorf W, Zelger BG, et al. Acute febrile neutrophilic dermatosis: a histopathologic study of 31 cases with review of literature. Am J Dermatopathol. 2007;29:125-133. doi:10.1097/01.dad.0000249887.59810.76
  5. Wilson TC, Stone MS, Swick BL. Histiocytoid Sweet syndrome with haloed myeloid cells masquerading as a cryptococcal infection. Am J Dermatopathology. 2014;36:264-269. doi:10.1097/DAD.0b013e31828b811b
  6. Guarner J, Brandt ME. Histopathologic diagnosis of fungal infections in the 21st century. Clin Microbiol Rev. 2011;24:247-280. doi:10.1128/CMR.00053-10
  7. Schneider JW, Jordaan HF, Geiger DH, et al. Erythema induratum of Bazin: a clinicopathological study of 20 cases of Mycobacterium tuberculosis DNA in skin lesions by polymerase chain reaction. Am J Dermatopathol. 1995;17:350-356. doi:10.1097/00000372-199508000-00008
  8. Boonchai W, Suthipinittharm P, Mahaisavariya P. Panniculitis in tuberculosis: a clinicopathologic study of nodular panniculitis associated with tuberculosis. Int J Dermatol. 1998;37:361-363. doi:10.1046/j.1365-4362.1998.00299.x
  9. Segura S, Pujol RM, Trindade F, et al. Vasculitis in erythema induratum of Bazin: a histopathologic study of 101 biopsy specimens from 86 patients. J Am Acad Dermatol. 2008;59:839-851. doi:10.1016/j.jaad.2008.07.030
  10. Ishiguro N, Kawashima M. Cutaneous polyarteritis nodosa: a report of 16 cases with clinical and histopathological analysis and a review of the published work. J Dermatol. 2010;37:85-93. doi:10.1111/j.1346-8138.2009.00752.x
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A 66-year-old man presented with new tender erythematous papules scattered over the arms and legs. A biopsy of a lesion on the left thigh was performed.

H&E, original magnification ×40 (inset: H&E, original magnification ×400).

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