- Email: [email protected]
Neoplastic erythema nodosum
Journal of the American Academy of Dermatology Volume 32, Number 2, Part 2
Matsuoka
22. Hammer GS, Bottone EJ, Hirschman SZ. Mucormycosis in a transplant recipient. Am J Clin Path011975;64:389-98. 23. Bennett JE. Chemotherapy of systemic mycosis. N Engl J Med 1974;290:30-2. 24. Stevens DA. Miconazole in the treatment of systemic fungal infections. Am Rev Respir Dis 1977;116:801-6. 25. Abramson E, Wilson D, Arky RA. Rhinocerebral phycomycosis in association with diabetic detoacidosis. Report of two cases and a review of clinical and experimental experience with amphotericin B therapy. Ann Intern Med 1967;66:735-42. 26. Battock DJ, Grausz H, Bobrowsky M, et al. Alternate-day amphotericin B therapy in the treatment of rhinocerebral phycomycosis (mucormycosis). Ann Intern Med 1968; 68:122-37. 27. Pillsbury HC, Fischer ND. Rhinocerebral mucormycosis. Arch Otolaryngol 1977;103:600-4. 28. Sugar AM. Interactions of amphotericin B and SCH 39304
in the treatment of experimental murine candidiasis: lack of antagonism of a polyene-azole combination. Antimicrob Agents Chemother 1991;35:1669-71. 29. Bruck HM, Nash G, Foley FD, et al. Opportunistic fungal infection in the burn wound with phycomycetes and Aspergillus. A clinical-pathologic review. Arch Surg 1971; 102:476-80. 30. ThomfordJW, WhittleseyD, EllnerJJ, et al. Invasiveprimary cutaneous phycomycosis in diabeticlegulcers.Arch Surg 1980;115:770-1. 31. BakerRD. Mucormycosis-a newdisease. JAMA 1957; 163:805-g. 32. GaleGR, WelchAM. Studieson opportunisticfungi. Inhibitionof Rhizopus oryzae by humanserum.Am J Mcd
Sci 1961;241:604-12. 33. Parfrey NA. Improveddiagnosisand prognosisof mucormycosis. A clinicopathologic studyof 33cases. Medicine 1986;65:113-23.
Neoplastic erythema nodosum Lois Y. Matsuoka,
MD Philadelphia,
Pennsylvania
We performed immunohistologicstudieson a 75-year-old white woman with erythema nodosum(EN) and a systemic lymphoma. A skin biopsy specimen from an EN lesion showed
lobular and septal pannicular infiltration by atypical lymphocytes. The cutaneous lymphocytic infiltrate wascomposed of a monoclonal population of B cells with X light chains. Atypical lymphocytes were alsoseenin the peripheral blood, and flow cytometry showeda pre-
dominance of the same phenotype of B cells with X light chains. Chemotherapy for systemic B-cell lymphoma resulted in the simultaneous resolution of EN and the lymphoma. This is the first documentation of EN representing direct cutaneous invasion by a B-cell lymphoma. (J AM ACAD DERMATOL1995;32:361-3.) Erythema nodosum (EN) is rarely associated with an internal malignancy.‘-11 Of these, the most common is a lymphoma, although the EN lesions demonstrate a characteristic septal lymphohistiocytic infiltrate similar to nonmalignant EN. 1-l 1 This article describes a patient with EN whose cutaneous lymphocytic infiltration was produced by atypical B lymphocytes of the X light chain type. Further investigations revealed a systemic lymphoma, and in addition, abundant atypical B lymphocytes with X light chains in peripheral blood. From the Department of Dermatology, Thomas Jefferson University. Repriit requests: Lois Y. Matsuoka, 211 South 9th St., PhiladeIphia, Copyright
Jefferson
MD, Department PA 19107.
@ 1995 by the American Academy 0190-9622/95 $3.00 + 0 16/4/57558
Medical
College,
of Dermatology,
of Dermatology,
CASE REPORT
A 75-year-old white woman had recurrent tender erythematous nodules of the lower legs for 8 months. She also had progressive fatigue and a weight loss of 8 pounds. According to the patient, hematologic tests and a bone marrow biopsy had been performed previously but the results (unavailable) had been “inconclusive.” Examination showed lesions typical of EN in the pretibial areas. Results of laboratory investigations were as follows: hemoglobin, 11.7 gm/dl; hematocrit, 34.7%; platelets, 12 1,000/mm3; white blood cell count, 9500/ mm3 with a differential of 13% neutrophils, 5% bands, 8 1% lymphocytes with 36% atypical forms, and 1% monocytes. Serum protein electrophoresis demonstrated a monoclonal peak in the y region. Computed tomographic scan of the abdomen showed splenomegaly and enlargedintraabdominal lymph nodes.
Inc.
A biopsy specimen of a skin nodule showed a septal and lobular panniculitis. The cellular infiltrate consisted of 361
362
Matsuoka
uniform-appearing mononuclear cells, suggestive of a small cell lymphoma of low-grade malignancy. Neither phagocytic histiocytes nor tissue necrosis were apparent. Immunohistochemical studies of skin were performed on a specimen that had been snap-frozen in liquid nitrogen immediately after removal and stored at - 70” C until analysis. Immunostaining was performed by the alkaline phosphatase-antialkaline phosphatase labeling method.12 The antibody test battery consisted of Weber primary mouse monoclonal antibodies (Dako Patts, Santa Barbara, Calif.) specific for the following surface cell antigens: CD2 (pan-T cell), CD3 (pan-T cell), CD4/5 (leukocyte common antigen), CD19 (pan-B cell), CD22 (pan-B cell), CD37 (B cell), IgM, K light chain, X light chain, and cytokeratin.t2 A preparation of whole blood lysed of red blood cells was used for flow cytometry analysis. The following surface markers were tested: CD2+ (total T cells), CD2’CD25+ (interleukin 2-activated cells), CD3+ (total T cells), CD3+DRf (activated T cells), CD4+ (helper/inducer cells), CD8+ (suppressor/cytotoxic cells), CD19+ (total B cells), CD16+CD56+ (natural killer cells), CD20f (total B cells), CD20CD5’ (total T cells), CD20fCD5+ (CD20+CD5+ cells), K+CD~~+ (K+ B cells), XfC9 19’ (X+ B cells) IgM+CD19’ (IgM+ B cells), IgD+CD19+ (IgD+ B cells), IgGfCD19+ (IgG+ B cells), IgAfCD19+ (IgA+ B cells). RESULTS
Skin lymphocytes from an EN lesion expressed almost exclusively B-cell surface markers: CD22, CD37, and CD19. A monoclonal origin for these lymphocytes was supported by the exclusive expression of X light chains; there was absence of IgM and K light chains. Lymphocytes that would express any of the T-cell markers CD2, CD3, and CD5 were not detected. Lymphocyte proliferative capacity, determined with monoclonal Ki-67, showed positive staining in 10% of the cells representing moderate-grade malignancy (nonneoplastic cells do not stain; staining of high-grade malignancy > 20%). Flow cytometry of blood lymphocytes showed B-cell predominance, with a relative B-cell count (CD19’) of 83% (normal, 7% to 17%). The T-cell count (CD3+) was correspondingly decreased to 10% (normal, 56% to 77%). B-cell phenotypes with high frequencies were as follows: X+ B cells (X+CD19’), 76%, and IgGf B cells (IgGf CD19+), 75%. A low frequency (less than 1%) was detected for each of the following B-cell phenotypes: K+ B cells (~+cD19+), IgM+ B cells (IgM+CD19+), IgD+ B cells (IgD+CD19+), and IgA+ B cells (IgA+CDl9+). Testing for specific T-cell surface markers showed the following phenotype frequencies: T cells positive for erythrocyte rosetting (CD2+), 14%; natural killer cells (CD16+-CD56’), 6%; interleukin 2-activated cells
Journal of the American Academy of Dermatology February 1995 (CD2+-CD25+), 5%; and activated T cells (CD3+DR+), 2%. Overall the pattern of peripheral blood indicated a monoclonal population of B cells expressing the phenotype CD19+, CD20f, CD22+, IgG+, and X light chain. It wasconcluded that the findings were diagnostic of a B-cell lymphoma of low-grade malignancy, stage IV.
Disease course Treatment consisted of a 5-day course of fludarabine, repeated after 1 month. The skin lesions regressed markedly after the first course of treatment and resolved completely after the second course. This was accompanied by simultaneous disappearance of lymphoma cells in the peripheral blood. DISCUSSION
This case representsthe first observation of atypical lymphocytes in the subcutaneous tissue of EN lesions. The temporal association between the EN and systemiclymphoma was clearly suggestive of a causative relation. In addition, initiation of specific chemotherapy resulted in disappearance of lymphoma cells from the blood and resolution of the cutaneous lesions.However, it was only the combination of histologic and phenotypic studies that identified the lymphomatous nature of the cutaneous lymphocytes. The link between the two conditions was definitely confirmed by the finding of the sameneoplastic monoclonal B cell with Xlight chain in both skin and peripheral blood. A review of the English medical literature on lymphomas shows that they are rarely associated with EN.3-11 Of note, EN usually precedesthe recognition of lymphoma, by a period ranging from 1 week to 12 months. This frequent delay in the recognition of the lymphoma is probably attributable to its sharing of clinical manifestations with EN. For instance, malaise, fever, and arthralgias may be referable to either lymphoma or EN. However, when systemicchemotherapy for lymphoma has been administered successfully, there has been a simultaneous resolution of the cutaneous lesions.3$7l‘, lo Lymphomas are associatedwith cutaneous manifestations in up to 50% of cases. These have been
classified into neoplastic (with histologic features of the lymphoma), paraneoplastic (nonneoplastic features but lymphoma dependent), and nonspecific.13-20 Neoplastic lymphomatous skin lesions are caused by direct infiltration by the malignancy and are manifest as solitary painless nodules, papules, or
Journal of the American Academy of Dermatology Volume 32, Number 2, Part 2
plaques with an erythematous or violaceous hue. This appearance may be similar to febrile nonsuppurative panniculitis, as reported in a patient with metastatic soft tissue sarcoma.21 The location of lymphomatous infiltrates has been variable, with cellular depositsfound anywhere from the papillary dermis to the subcutaneous fascia.t3*16 The findings in our patient indicate that EN should also be included among the neoplastic manifestations of lymphoma. I thank Roland Schwarting, MD, and Jose Martinez, MD, for their help in performing the histochemical and flow cytometry studies. REFERENCES
1. GordonH. Erythemanodosum: a reviewof onehundred andfifteen cases. Br J Dermatol1961;73:393-409. 2. SamsWM, WinkelmannRK. Theassociation of erythema ncdosumwith ulcerativecolitis. South Med J 1968;61: 676-9. 3. SimonS,AzevedoSJ, ByrnesJJ. Erythemanodosum heraldingrecurrentHodgkin’sdisease.Cancer 1985;56:1470-2. 4. FraserJ. A casefor diagnosis (erythemanodosum?). Arch DermatolSyph 1936;34:1080. 5. ChalmersRJG, Proctor SJ, Marks JM. Erythema nodosumand Hodgkin’sdisease. Br J Dermatol1982;106: 593-5. 6. Taylor F. The chronicrelapsingpyrexia of Hodgkin’sdisease.Guy’sHospRep (Land) 1906;60:3-3 1. 7. ParodiA, CestariR, ReboraA. Erythemanodosum asthe presentingsymptomof gastriccentrofollicularlymphoma. Int J Dermatol1989;28:336-7.
Matsuoka
363
8. Junta J, Flores A, Ojanguren I, et al. Erythema nodosum and Lennert’s lymphoma. Clin Lab Haematol 1986;8: 266-7. 9. ThomsonGTD, Keystone EC, Sturgeon JFG, et al. Erythemanodosumandnon-Hodgkin’s lymphoma.J Rheumatol 1990;17:383-5. and 10. ReverterJC, CocaJ, Font J, et al. Erythemanodosum pulmonarysolitary noduleasthe first manifestations of non-Hodgkin’s lymphoma.Br J DisChest1987;81:397-9. 11. Fuller CJ. Hodgkin’sdisease with erythemanodosum. Br Med J 1934;11:1172-3. 12. CordellJL, FaliniB, ErberWN, et al. Immunoenzymatic labelingof monoclonal antibodies usingimmunecomplexes of alkalinephosphatase andmonoclonal anti-alkalinephosphatase(APAAP complexes).J HistochemCytochem 1984;32:219-29. 13. EptseinE,MacEachernK. Dermatologic manifestations of the lymphoblastoma-leukemia group. Arch Intern Med 1937;60:867-75. 14. SmithJL, ButlerJJ.Skininvolvementin Hodgkin’sdisease. Cancer1980;45:354-61. 15. White RM, PattersonJW. Cutaneousinvolvementin Hodgkin’sdisease. Cancer1985;55:1136-45. 16. LongJC, Mihm MC, Qazi R. Malignantlymphomaof the skin.Cancer1976;38:1282-96. 17. Curth HO. Cancerassociated with acanthosis nigricans. Arch Surg 1943;47:5 17-52. 18. MatsuokaLY, WortsmanJ, GoldmanJ. Acanthosisnigricans.Clin Dermatol1993;11:21-5. 19. MatsuokaLY, WortsmanJ, Stanley JR. Epidermalautoantibodies in erythemamultiforme.JAM ACAD DERMATOL 1989;21:677-80. 20. Anhalt GJ, Kim S, StanleyJR, et al. Paraneoplastic pemphigus.N Engl J Med 1990;323:1729-35. 21. MarschWC, StuttgenG, WegenerHH. Panniculitisnodular%febrillisnonsuppurative in metastasizing soft-tissue sarcoma(in German).Hautarzt 1979;30:12-5.
Matsuoka
22. Hammer GS, Bottone EJ, Hirschman SZ. Mucormycosis in a transplant recipient. Am J Clin Path011975;64:389-98. 23. Bennett JE. Chemotherapy of systemic mycosis. N Engl J Med 1974;290:30-2. 24. Stevens DA. Miconazole in the treatment of systemic fungal infections. Am Rev Respir Dis 1977;116:801-6. 25. Abramson E, Wilson D, Arky RA. Rhinocerebral phycomycosis in association with diabetic detoacidosis. Report of two cases and a review of clinical and experimental experience with amphotericin B therapy. Ann Intern Med 1967;66:735-42. 26. Battock DJ, Grausz H, Bobrowsky M, et al. Alternate-day amphotericin B therapy in the treatment of rhinocerebral phycomycosis (mucormycosis). Ann Intern Med 1968; 68:122-37. 27. Pillsbury HC, Fischer ND. Rhinocerebral mucormycosis. Arch Otolaryngol 1977;103:600-4. 28. Sugar AM. Interactions of amphotericin B and SCH 39304
in the treatment of experimental murine candidiasis: lack of antagonism of a polyene-azole combination. Antimicrob Agents Chemother 1991;35:1669-71. 29. Bruck HM, Nash G, Foley FD, et al. Opportunistic fungal infection in the burn wound with phycomycetes and Aspergillus. A clinical-pathologic review. Arch Surg 1971; 102:476-80. 30. ThomfordJW, WhittleseyD, EllnerJJ, et al. Invasiveprimary cutaneous phycomycosis in diabeticlegulcers.Arch Surg 1980;115:770-1. 31. BakerRD. Mucormycosis-a newdisease. JAMA 1957; 163:805-g. 32. GaleGR, WelchAM. Studieson opportunisticfungi. Inhibitionof Rhizopus oryzae by humanserum.Am J Mcd
Sci 1961;241:604-12. 33. Parfrey NA. Improveddiagnosisand prognosisof mucormycosis. A clinicopathologic studyof 33cases. Medicine 1986;65:113-23.
Neoplastic erythema nodosum Lois Y. Matsuoka,
MD Philadelphia,
Pennsylvania
We performed immunohistologicstudieson a 75-year-old white woman with erythema nodosum(EN) and a systemic lymphoma. A skin biopsy specimen from an EN lesion showed
lobular and septal pannicular infiltration by atypical lymphocytes. The cutaneous lymphocytic infiltrate wascomposed of a monoclonal population of B cells with X light chains. Atypical lymphocytes were alsoseenin the peripheral blood, and flow cytometry showeda pre-
dominance of the same phenotype of B cells with X light chains. Chemotherapy for systemic B-cell lymphoma resulted in the simultaneous resolution of EN and the lymphoma. This is the first documentation of EN representing direct cutaneous invasion by a B-cell lymphoma. (J AM ACAD DERMATOL1995;32:361-3.) Erythema nodosum (EN) is rarely associated with an internal malignancy.‘-11 Of these, the most common is a lymphoma, although the EN lesions demonstrate a characteristic septal lymphohistiocytic infiltrate similar to nonmalignant EN. 1-l 1 This article describes a patient with EN whose cutaneous lymphocytic infiltration was produced by atypical B lymphocytes of the X light chain type. Further investigations revealed a systemic lymphoma, and in addition, abundant atypical B lymphocytes with X light chains in peripheral blood. From the Department of Dermatology, Thomas Jefferson University. Repriit requests: Lois Y. Matsuoka, 211 South 9th St., PhiladeIphia, Copyright
Jefferson
MD, Department PA 19107.
@ 1995 by the American Academy 0190-9622/95 $3.00 + 0 16/4/57558
Medical
College,
of Dermatology,
of Dermatology,
CASE REPORT
A 75-year-old white woman had recurrent tender erythematous nodules of the lower legs for 8 months. She also had progressive fatigue and a weight loss of 8 pounds. According to the patient, hematologic tests and a bone marrow biopsy had been performed previously but the results (unavailable) had been “inconclusive.” Examination showed lesions typical of EN in the pretibial areas. Results of laboratory investigations were as follows: hemoglobin, 11.7 gm/dl; hematocrit, 34.7%; platelets, 12 1,000/mm3; white blood cell count, 9500/ mm3 with a differential of 13% neutrophils, 5% bands, 8 1% lymphocytes with 36% atypical forms, and 1% monocytes. Serum protein electrophoresis demonstrated a monoclonal peak in the y region. Computed tomographic scan of the abdomen showed splenomegaly and enlargedintraabdominal lymph nodes.
Inc.
A biopsy specimen of a skin nodule showed a septal and lobular panniculitis. The cellular infiltrate consisted of 361
362
Matsuoka
uniform-appearing mononuclear cells, suggestive of a small cell lymphoma of low-grade malignancy. Neither phagocytic histiocytes nor tissue necrosis were apparent. Immunohistochemical studies of skin were performed on a specimen that had been snap-frozen in liquid nitrogen immediately after removal and stored at - 70” C until analysis. Immunostaining was performed by the alkaline phosphatase-antialkaline phosphatase labeling method.12 The antibody test battery consisted of Weber primary mouse monoclonal antibodies (Dako Patts, Santa Barbara, Calif.) specific for the following surface cell antigens: CD2 (pan-T cell), CD3 (pan-T cell), CD4/5 (leukocyte common antigen), CD19 (pan-B cell), CD22 (pan-B cell), CD37 (B cell), IgM, K light chain, X light chain, and cytokeratin.t2 A preparation of whole blood lysed of red blood cells was used for flow cytometry analysis. The following surface markers were tested: CD2+ (total T cells), CD2’CD25+ (interleukin 2-activated cells), CD3+ (total T cells), CD3+DRf (activated T cells), CD4+ (helper/inducer cells), CD8+ (suppressor/cytotoxic cells), CD19+ (total B cells), CD16+CD56+ (natural killer cells), CD20f (total B cells), CD20CD5’ (total T cells), CD20fCD5+ (CD20+CD5+ cells), K+CD~~+ (K+ B cells), XfC9 19’ (X+ B cells) IgM+CD19’ (IgM+ B cells), IgD+CD19+ (IgD+ B cells), IgGfCD19+ (IgG+ B cells), IgAfCD19+ (IgA+ B cells). RESULTS
Skin lymphocytes from an EN lesion expressed almost exclusively B-cell surface markers: CD22, CD37, and CD19. A monoclonal origin for these lymphocytes was supported by the exclusive expression of X light chains; there was absence of IgM and K light chains. Lymphocytes that would express any of the T-cell markers CD2, CD3, and CD5 were not detected. Lymphocyte proliferative capacity, determined with monoclonal Ki-67, showed positive staining in 10% of the cells representing moderate-grade malignancy (nonneoplastic cells do not stain; staining of high-grade malignancy > 20%). Flow cytometry of blood lymphocytes showed B-cell predominance, with a relative B-cell count (CD19’) of 83% (normal, 7% to 17%). The T-cell count (CD3+) was correspondingly decreased to 10% (normal, 56% to 77%). B-cell phenotypes with high frequencies were as follows: X+ B cells (X+CD19’), 76%, and IgGf B cells (IgGf CD19+), 75%. A low frequency (less than 1%) was detected for each of the following B-cell phenotypes: K+ B cells (~+cD19+), IgM+ B cells (IgM+CD19+), IgD+ B cells (IgD+CD19+), and IgA+ B cells (IgA+CDl9+). Testing for specific T-cell surface markers showed the following phenotype frequencies: T cells positive for erythrocyte rosetting (CD2+), 14%; natural killer cells (CD16+-CD56’), 6%; interleukin 2-activated cells
Journal of the American Academy of Dermatology February 1995 (CD2+-CD25+), 5%; and activated T cells (CD3+DR+), 2%. Overall the pattern of peripheral blood indicated a monoclonal population of B cells expressing the phenotype CD19+, CD20f, CD22+, IgG+, and X light chain. It wasconcluded that the findings were diagnostic of a B-cell lymphoma of low-grade malignancy, stage IV.
Disease course Treatment consisted of a 5-day course of fludarabine, repeated after 1 month. The skin lesions regressed markedly after the first course of treatment and resolved completely after the second course. This was accompanied by simultaneous disappearance of lymphoma cells in the peripheral blood. DISCUSSION
This case representsthe first observation of atypical lymphocytes in the subcutaneous tissue of EN lesions. The temporal association between the EN and systemiclymphoma was clearly suggestive of a causative relation. In addition, initiation of specific chemotherapy resulted in disappearance of lymphoma cells from the blood and resolution of the cutaneous lesions.However, it was only the combination of histologic and phenotypic studies that identified the lymphomatous nature of the cutaneous lymphocytes. The link between the two conditions was definitely confirmed by the finding of the sameneoplastic monoclonal B cell with Xlight chain in both skin and peripheral blood. A review of the English medical literature on lymphomas shows that they are rarely associated with EN.3-11 Of note, EN usually precedesthe recognition of lymphoma, by a period ranging from 1 week to 12 months. This frequent delay in the recognition of the lymphoma is probably attributable to its sharing of clinical manifestations with EN. For instance, malaise, fever, and arthralgias may be referable to either lymphoma or EN. However, when systemicchemotherapy for lymphoma has been administered successfully, there has been a simultaneous resolution of the cutaneous lesions.3$7l‘, lo Lymphomas are associatedwith cutaneous manifestations in up to 50% of cases. These have been
classified into neoplastic (with histologic features of the lymphoma), paraneoplastic (nonneoplastic features but lymphoma dependent), and nonspecific.13-20 Neoplastic lymphomatous skin lesions are caused by direct infiltration by the malignancy and are manifest as solitary painless nodules, papules, or
Journal of the American Academy of Dermatology Volume 32, Number 2, Part 2
plaques with an erythematous or violaceous hue. This appearance may be similar to febrile nonsuppurative panniculitis, as reported in a patient with metastatic soft tissue sarcoma.21 The location of lymphomatous infiltrates has been variable, with cellular depositsfound anywhere from the papillary dermis to the subcutaneous fascia.t3*16 The findings in our patient indicate that EN should also be included among the neoplastic manifestations of lymphoma. I thank Roland Schwarting, MD, and Jose Martinez, MD, for their help in performing the histochemical and flow cytometry studies. REFERENCES
1. GordonH. Erythemanodosum: a reviewof onehundred andfifteen cases. Br J Dermatol1961;73:393-409. 2. SamsWM, WinkelmannRK. Theassociation of erythema ncdosumwith ulcerativecolitis. South Med J 1968;61: 676-9. 3. SimonS,AzevedoSJ, ByrnesJJ. Erythemanodosum heraldingrecurrentHodgkin’sdisease.Cancer 1985;56:1470-2. 4. FraserJ. A casefor diagnosis (erythemanodosum?). Arch DermatolSyph 1936;34:1080. 5. ChalmersRJG, Proctor SJ, Marks JM. Erythema nodosumand Hodgkin’sdisease. Br J Dermatol1982;106: 593-5. 6. Taylor F. The chronicrelapsingpyrexia of Hodgkin’sdisease.Guy’sHospRep (Land) 1906;60:3-3 1. 7. ParodiA, CestariR, ReboraA. Erythemanodosum asthe presentingsymptomof gastriccentrofollicularlymphoma. Int J Dermatol1989;28:336-7.
Matsuoka
363
8. Junta J, Flores A, Ojanguren I, et al. Erythema nodosum and Lennert’s lymphoma. Clin Lab Haematol 1986;8: 266-7. 9. ThomsonGTD, Keystone EC, Sturgeon JFG, et al. Erythemanodosumandnon-Hodgkin’s lymphoma.J Rheumatol 1990;17:383-5. and 10. ReverterJC, CocaJ, Font J, et al. Erythemanodosum pulmonarysolitary noduleasthe first manifestations of non-Hodgkin’s lymphoma.Br J DisChest1987;81:397-9. 11. Fuller CJ. Hodgkin’sdisease with erythemanodosum. Br Med J 1934;11:1172-3. 12. CordellJL, FaliniB, ErberWN, et al. Immunoenzymatic labelingof monoclonal antibodies usingimmunecomplexes of alkalinephosphatase andmonoclonal anti-alkalinephosphatase(APAAP complexes).J HistochemCytochem 1984;32:219-29. 13. EptseinE,MacEachernK. Dermatologic manifestations of the lymphoblastoma-leukemia group. Arch Intern Med 1937;60:867-75. 14. SmithJL, ButlerJJ.Skininvolvementin Hodgkin’sdisease. Cancer1980;45:354-61. 15. White RM, PattersonJW. Cutaneousinvolvementin Hodgkin’sdisease. Cancer1985;55:1136-45. 16. LongJC, Mihm MC, Qazi R. Malignantlymphomaof the skin.Cancer1976;38:1282-96. 17. Curth HO. Cancerassociated with acanthosis nigricans. Arch Surg 1943;47:5 17-52. 18. MatsuokaLY, WortsmanJ, GoldmanJ. Acanthosisnigricans.Clin Dermatol1993;11:21-5. 19. MatsuokaLY, WortsmanJ, Stanley JR. Epidermalautoantibodies in erythemamultiforme.JAM ACAD DERMATOL 1989;21:677-80. 20. Anhalt GJ, Kim S, StanleyJR, et al. Paraneoplastic pemphigus.N Engl J Med 1990;323:1729-35. 21. MarschWC, StuttgenG, WegenerHH. Panniculitisnodular%febrillisnonsuppurative in metastasizing soft-tissue sarcoma(in German).Hautarzt 1979;30:12-5.