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Cutaneous large-cell lymphoma histologically resembling sarcoidosis
Cutaneous large-cell lymphoma histologically resembling sarcoidosis Irmina Boulier, MD, Jonathan Cohen, MD, and Francisco A. Kerdel, BSc, MB, BS
Miami, Florida A case of cutaneous T-cell lymphoma with histologic characteristics of sarcoidosis is reported. Although the patient responded to chemotherapy, a subsequent relapse and the eventual death of the patient underscores the aggressive nature of this condition. (J AM ACAD DERMATOL 1993;28:327-30.)
The presence of noncaseating epithelioid cell granulomas generates a broad differential diagnosis that includes infectious and noninfectious causes. We describe an elderly woman whose cutaneous granulomas were caused by large-cell lymphoma. CASE REPORT An 86-year-old white woman had a 5-month history of asymptomatic, scattered, red-purple nodules. The lesions first appeared on the feet and later involved the lower extremities and trunk. The paient showed no evidence of systemic illness. Examination revealed multiple red-to-violaceous nodules on the dorsum of the feet, lower extremities, face, neck, and back (Figs. 1 and 2). No palpable lymphadenopathy or hepatosplenomegaly was found. Results of routine laboratory studies were normal except for slightly elevated levels of alkaline phosphatase and lactate dehydrogenase. A chest roentgenogram showed bilateral atelectasis. Serum protein electrophoresis revealed a monoclonal IgA->' gammopathy, but results of a urine examination were negative for Bence Jones protein. Findings of a bone marrow biopsy specimen and computerized tomographic scans of the abdomen and pelvis were normal. Results of a biopsy specimen showed superficial and deep dermal perivascular mononuclear cell infiltration with noncaseating granulomas (Fig. 3). Fungal, bacterial, and mycobacterial stains and cultures were negative. The patient continued to develop lesions. Results of repeat biopsy specimens showed granulomatous features, but some also had an atypicallymphoreticular perivascular infiltrate (Fig. 4). Immunohistochemical studies From the Department of Dermatology and Cutaneous Surgery, University of Miami, and the Department of Medicine, Division of Hematology and Oncology, Cedars Medical Center. Reprints not available. Copyright ® 1993 by the American Academy of Dermatology. 0190-9622/93 $1.00+ ,1016/4/39260
Fig. 1. Dorsa of feet with multiple red-to-violaceous nodules. showed that the cellular infiltrate was strongly positive for CD antigens 2, 3,4,5, 8, and 30 (Ki-I). T-cell receptor gene rearrangement studies supported the T-cell monoclonality of the infiltrate (complimentary DNA probes CT-B, JB I, and JB II were used, with EcoRI digestion). A diagnosis of large-cell anaplastic (Ki-l +) lymphoma was made. l , 2 Therapy was begun with topical BeND (carmustine), which was applied to several lesions on the left side and topical nitrogen mustard, which was applied to several
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328 Boulier et al.
Fig. 2. Scattered nodules and plaques on face. lesions on the right side. In addition, the patient was given etretinate orally.3, 4 Her lesions continued to progress; thus she was treated with cyclophosphamide, etoposide (VP-16), procarbazine, and prednisone (CEPp).5 After three cycles of therapy almost complete resolution was achieved. Chemotherapy was discontinued, but the patient had a relapse within 8 weeks. Reinduction again resulted in partial remission, butthe patient died shortly thereafter, possibly from sepsis. A postmortem examination was not performed. DISCUSSION
The non-Hodgkin's lymphomas are classified on the basis of architectural and cytologic features. The architecture can be nodular (follicle-like) or diffuse. The cytology of non-Hodgkin's lymphoma cells, by light microscopic examination, can range from small lymphocyte-like cells to larger cells; either can have elefted or nonelefted nuclei. Immunophenotyping and T-cell receptor gene rearrangement are now used for more specific identification of B- and T-cell malignancies. In our patient no nodal or other systemic involvement was detected, but the perivascular infiltrate in the skin biopsy specimen was grossly atypical,
Journal of the American Academy of Dermatology February 1993
Immunophenotyping showed that 20% of this cellular infiltrate was positive for the Ki-l or CD30 antigen, a marker associated with large-cell anaplastic lymphoma. In general the Ki-l antigen labels activated T and B lymphocytes and may be expressed in inflammatory cell infiltrates, lymphomatoid papulosis, and both T- and B-celllymphoma with "activated" phenotypes,l· 2 T-cell receptor gene rearrangement studies were consistent with a clonal T-celllymphoproliferative process. The infiltrating cells were also positive for CD 2,3,4,5, and 8. This mixed phenotypic marker expression is probably related to the inflammatory infiltrate associated with malignant cells or sarcoidal granulomas. We believe our patient had a large-cell anaplastic (Ki-l +) lymphoma of T-cell origin with reactive granulomatous inflammation. The reason for the concomitant presence of sareoidal granulomas remains unclear, but we conjecture that they represent a reactive phenomenon to the infiltrating malignant cells. Other cases of malignant non-Hodgkin's lymphoma with cutaneous granulomas have been reported. Randle et al. 6 reported two cases of dermal and subcutaneous epithelioid granulomatous masses. Only after a long search for infectious causes was lymphoma discovered in a lymph node biopsy specimen in these patients. Diette et aU described a patient with fever, malaise, weight loss, and a cough who developed cutaneous nodules. Results of cutaneous biopsy specimens were interpreted as granulomatous inflammation consistent with a sarcoidal reaction. The diagnosis of lymphoma was made only after his neurologic deterioration led to the discovery of a large-cell lymphoma in the brain. The cutaneous granulomas were believed to represent a "nonspecific immune response," possibly related to the underlying lymphoma. Braylan et a1. 8 reported three cases of an unusual B-cell lymphoma with splenomegaly but without cutaneous manifestations. Multiple epithelioid granulomas were present in the spleen. These cases also represent an association between exuberant epithelioid granulomas and an underlying neoplastic lymphoid proliferation. These patients showed abnormalities of serum immunoglobulins. Our patient also had an IgA-A. spike. Nonnecrotic epithelioid cell granulomas are unusual in non-Hodgkin's lymphomas but are more common in Hodgkin's disease,8-10 where they may
Journal of the American Academy of Dermatology Volume 28, Number 2, Part 2
Cutaneous large-cell lymphoma 329
Fig. 3. Superficial and deep dermal perivascular mononuclear cell infiltration with associated noncaseating granulomas.
Fig. 4. Atypical nuclei in perivascular mononuclear cell infiltrate.
imply a more favorable prognosis. I I, 12 Although the original description of granulomatous mycosis fungoides suggested a favorable prognosis, no such association has been noted in subsequent reports.B- 17 Whereas one fonn of cutaneous T-cell lymphoma, granulomatous slack skin, has an unusually chronic course, 17, 18 this contrasts with the aggressive cutaneous lymphoma with granulomatous features in our patient. In a recent study, 9 of 14 patients (64%) who received CEPP as first-line therapy for intermediate or high-grade non-Hodgkin's lymphomas responded
completely. 1 Although this therapy induced a remission in our patient, it did not halt the ultimate progression of her disease. REFERENCES 1. Ralfldaer E, Bosq J, Gatter KC, et at. Expression of a Hodgkin and Reed-Sternberg cell associated antigen (Ki-l) in cutaneous lymphoid infiltrates. Arch Dermatol Res 1987;279:285-92. 2. Suchi T, LennertK, Tu L-Y, etal. Histopathology and immunohistochemistry of peripheral T-cell lymphomas: a proposal for their classification. J Clin PathoI1987;40:9951015. 3. Claudy AL, Rouchouse B, Boucheron S, et al. Treatment
Journal of the American Academy of Dermatology February 1993
330 Boulier et al.
4.
5. 6. 7. 8. 9. 10.
of cutaneous lymphoma with etretinate. Br J Dermatol 1983;109:49-56. Chow JM, Cheng AL, Su Il, et a1. 13-cis-retinoic acid induces cellular differentiation and durable remission in refractory cutaneous Ki-l lymphoma. Cancer 1991;67: 2490-4. Chao N J, Rosenberg SA, Horning SJ. CEPP(B): an effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin's lymphoma. Blood 1990;76:1293-8. Randle HW, Banks PM, Winkleman RK. Cutaneous granulomas in malignant lymphoma. Arch Dermatol 1980;116:441-3. Diette KM, Caro WA, Roegnik HH. Malignant lymphoma presenting with cutaneous granulomas. J AM ACAD DERMATOL 1984;10:896-902. Braylan RC, Long JC, Jaffe ES, et a1. Malignant lymphoma obscured by concomitant extensive epithelioid granulomas. Cancer 1977;39:1146-55. Goldfarb BL, Summer SC. Coexistent disseminated sarcoidosis and Hodgkin's disease. JAMA 1970;211:1525-8. Kadin ME, Donaldson SS, Dorfman RF. Isolated granulomas in Hodgkin's disease. N Engl J Med 1970;283:85961.
11. O'Connell MJ, Schimpff SC, Kirschner RH, et al. Epithelioid granulomas in Hodgkin's disease: a favorable prognostic sign? JAMA 1975;233:886-9. 12. Sacks EL, Donaldson SS, Gordon J, et a1. Epithelioid granulomas associated with Hodgkin's disease: clinical correlations in 55 previously untreated patients. Cancer 1978;41:562-5. 13. Dabski K, Stoll HL. Granulomatous reactions in mycosis fungoides. J Surg OncoI1987;34:217-29. 14. Schwartz RA, Burgess GR, Holterman 0, et a1. Mycosis fungoides associated with florid sarcoid reactions. J Surg OncoI1980;14:347-57. 15. LeBoit PE, Zackheim HS, White CR. Granulomatous variants of cutaneous T-cell lymphoma. Am J Surg Pathol 1988;12:83-95. 16. Garrie SA, Hirsch P, Levan N. Granuloma annulare-like pattern in mycosis fungoides. Arch Dermatol 1972;105: 717-9. 17. Balus L, Bassetti F, Gentili G. Granulomatous slack skin. Arch DermatoI1985;121:250-2. 18. Ackerman AB, F1axman BA. Granulomatous mycosis fungoides. Br J DermatoI1970;82:397-401.
CORRECTION
In the article "Aneurysm in the skin: Arterial fibromuscular dysplasia," by Kanzaki et a1., which appeared in the November 1992 Case Reports supplement, volume 27, number 5, part 2, the legends for Figures 2 and 3 on page 884 were transposed.
Miami, Florida A case of cutaneous T-cell lymphoma with histologic characteristics of sarcoidosis is reported. Although the patient responded to chemotherapy, a subsequent relapse and the eventual death of the patient underscores the aggressive nature of this condition. (J AM ACAD DERMATOL 1993;28:327-30.)
The presence of noncaseating epithelioid cell granulomas generates a broad differential diagnosis that includes infectious and noninfectious causes. We describe an elderly woman whose cutaneous granulomas were caused by large-cell lymphoma. CASE REPORT An 86-year-old white woman had a 5-month history of asymptomatic, scattered, red-purple nodules. The lesions first appeared on the feet and later involved the lower extremities and trunk. The paient showed no evidence of systemic illness. Examination revealed multiple red-to-violaceous nodules on the dorsum of the feet, lower extremities, face, neck, and back (Figs. 1 and 2). No palpable lymphadenopathy or hepatosplenomegaly was found. Results of routine laboratory studies were normal except for slightly elevated levels of alkaline phosphatase and lactate dehydrogenase. A chest roentgenogram showed bilateral atelectasis. Serum protein electrophoresis revealed a monoclonal IgA->' gammopathy, but results of a urine examination were negative for Bence Jones protein. Findings of a bone marrow biopsy specimen and computerized tomographic scans of the abdomen and pelvis were normal. Results of a biopsy specimen showed superficial and deep dermal perivascular mononuclear cell infiltration with noncaseating granulomas (Fig. 3). Fungal, bacterial, and mycobacterial stains and cultures were negative. The patient continued to develop lesions. Results of repeat biopsy specimens showed granulomatous features, but some also had an atypicallymphoreticular perivascular infiltrate (Fig. 4). Immunohistochemical studies From the Department of Dermatology and Cutaneous Surgery, University of Miami, and the Department of Medicine, Division of Hematology and Oncology, Cedars Medical Center. Reprints not available. Copyright ® 1993 by the American Academy of Dermatology. 0190-9622/93 $1.00+ ,1016/4/39260
Fig. 1. Dorsa of feet with multiple red-to-violaceous nodules. showed that the cellular infiltrate was strongly positive for CD antigens 2, 3,4,5, 8, and 30 (Ki-I). T-cell receptor gene rearrangement studies supported the T-cell monoclonality of the infiltrate (complimentary DNA probes CT-B, JB I, and JB II were used, with EcoRI digestion). A diagnosis of large-cell anaplastic (Ki-l +) lymphoma was made. l , 2 Therapy was begun with topical BeND (carmustine), which was applied to several lesions on the left side and topical nitrogen mustard, which was applied to several
327
328 Boulier et al.
Fig. 2. Scattered nodules and plaques on face. lesions on the right side. In addition, the patient was given etretinate orally.3, 4 Her lesions continued to progress; thus she was treated with cyclophosphamide, etoposide (VP-16), procarbazine, and prednisone (CEPp).5 After three cycles of therapy almost complete resolution was achieved. Chemotherapy was discontinued, but the patient had a relapse within 8 weeks. Reinduction again resulted in partial remission, butthe patient died shortly thereafter, possibly from sepsis. A postmortem examination was not performed. DISCUSSION
The non-Hodgkin's lymphomas are classified on the basis of architectural and cytologic features. The architecture can be nodular (follicle-like) or diffuse. The cytology of non-Hodgkin's lymphoma cells, by light microscopic examination, can range from small lymphocyte-like cells to larger cells; either can have elefted or nonelefted nuclei. Immunophenotyping and T-cell receptor gene rearrangement are now used for more specific identification of B- and T-cell malignancies. In our patient no nodal or other systemic involvement was detected, but the perivascular infiltrate in the skin biopsy specimen was grossly atypical,
Journal of the American Academy of Dermatology February 1993
Immunophenotyping showed that 20% of this cellular infiltrate was positive for the Ki-l or CD30 antigen, a marker associated with large-cell anaplastic lymphoma. In general the Ki-l antigen labels activated T and B lymphocytes and may be expressed in inflammatory cell infiltrates, lymphomatoid papulosis, and both T- and B-celllymphoma with "activated" phenotypes,l· 2 T-cell receptor gene rearrangement studies were consistent with a clonal T-celllymphoproliferative process. The infiltrating cells were also positive for CD 2,3,4,5, and 8. This mixed phenotypic marker expression is probably related to the inflammatory infiltrate associated with malignant cells or sarcoidal granulomas. We believe our patient had a large-cell anaplastic (Ki-l +) lymphoma of T-cell origin with reactive granulomatous inflammation. The reason for the concomitant presence of sareoidal granulomas remains unclear, but we conjecture that they represent a reactive phenomenon to the infiltrating malignant cells. Other cases of malignant non-Hodgkin's lymphoma with cutaneous granulomas have been reported. Randle et al. 6 reported two cases of dermal and subcutaneous epithelioid granulomatous masses. Only after a long search for infectious causes was lymphoma discovered in a lymph node biopsy specimen in these patients. Diette et aU described a patient with fever, malaise, weight loss, and a cough who developed cutaneous nodules. Results of cutaneous biopsy specimens were interpreted as granulomatous inflammation consistent with a sarcoidal reaction. The diagnosis of lymphoma was made only after his neurologic deterioration led to the discovery of a large-cell lymphoma in the brain. The cutaneous granulomas were believed to represent a "nonspecific immune response," possibly related to the underlying lymphoma. Braylan et a1. 8 reported three cases of an unusual B-cell lymphoma with splenomegaly but without cutaneous manifestations. Multiple epithelioid granulomas were present in the spleen. These cases also represent an association between exuberant epithelioid granulomas and an underlying neoplastic lymphoid proliferation. These patients showed abnormalities of serum immunoglobulins. Our patient also had an IgA-A. spike. Nonnecrotic epithelioid cell granulomas are unusual in non-Hodgkin's lymphomas but are more common in Hodgkin's disease,8-10 where they may
Journal of the American Academy of Dermatology Volume 28, Number 2, Part 2
Cutaneous large-cell lymphoma 329
Fig. 3. Superficial and deep dermal perivascular mononuclear cell infiltration with associated noncaseating granulomas.
Fig. 4. Atypical nuclei in perivascular mononuclear cell infiltrate.
imply a more favorable prognosis. I I, 12 Although the original description of granulomatous mycosis fungoides suggested a favorable prognosis, no such association has been noted in subsequent reports.B- 17 Whereas one fonn of cutaneous T-cell lymphoma, granulomatous slack skin, has an unusually chronic course, 17, 18 this contrasts with the aggressive cutaneous lymphoma with granulomatous features in our patient. In a recent study, 9 of 14 patients (64%) who received CEPP as first-line therapy for intermediate or high-grade non-Hodgkin's lymphomas responded
completely. 1 Although this therapy induced a remission in our patient, it did not halt the ultimate progression of her disease. REFERENCES 1. Ralfldaer E, Bosq J, Gatter KC, et at. Expression of a Hodgkin and Reed-Sternberg cell associated antigen (Ki-l) in cutaneous lymphoid infiltrates. Arch Dermatol Res 1987;279:285-92. 2. Suchi T, LennertK, Tu L-Y, etal. Histopathology and immunohistochemistry of peripheral T-cell lymphomas: a proposal for their classification. J Clin PathoI1987;40:9951015. 3. Claudy AL, Rouchouse B, Boucheron S, et al. Treatment
Journal of the American Academy of Dermatology February 1993
330 Boulier et al.
4.
5. 6. 7. 8. 9. 10.
of cutaneous lymphoma with etretinate. Br J Dermatol 1983;109:49-56. Chow JM, Cheng AL, Su Il, et a1. 13-cis-retinoic acid induces cellular differentiation and durable remission in refractory cutaneous Ki-l lymphoma. Cancer 1991;67: 2490-4. Chao N J, Rosenberg SA, Horning SJ. CEPP(B): an effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin's lymphoma. Blood 1990;76:1293-8. Randle HW, Banks PM, Winkleman RK. Cutaneous granulomas in malignant lymphoma. Arch Dermatol 1980;116:441-3. Diette KM, Caro WA, Roegnik HH. Malignant lymphoma presenting with cutaneous granulomas. J AM ACAD DERMATOL 1984;10:896-902. Braylan RC, Long JC, Jaffe ES, et a1. Malignant lymphoma obscured by concomitant extensive epithelioid granulomas. Cancer 1977;39:1146-55. Goldfarb BL, Summer SC. Coexistent disseminated sarcoidosis and Hodgkin's disease. JAMA 1970;211:1525-8. Kadin ME, Donaldson SS, Dorfman RF. Isolated granulomas in Hodgkin's disease. N Engl J Med 1970;283:85961.
11. O'Connell MJ, Schimpff SC, Kirschner RH, et al. Epithelioid granulomas in Hodgkin's disease: a favorable prognostic sign? JAMA 1975;233:886-9. 12. Sacks EL, Donaldson SS, Gordon J, et a1. Epithelioid granulomas associated with Hodgkin's disease: clinical correlations in 55 previously untreated patients. Cancer 1978;41:562-5. 13. Dabski K, Stoll HL. Granulomatous reactions in mycosis fungoides. J Surg OncoI1987;34:217-29. 14. Schwartz RA, Burgess GR, Holterman 0, et a1. Mycosis fungoides associated with florid sarcoid reactions. J Surg OncoI1980;14:347-57. 15. LeBoit PE, Zackheim HS, White CR. Granulomatous variants of cutaneous T-cell lymphoma. Am J Surg Pathol 1988;12:83-95. 16. Garrie SA, Hirsch P, Levan N. Granuloma annulare-like pattern in mycosis fungoides. Arch Dermatol 1972;105: 717-9. 17. Balus L, Bassetti F, Gentili G. Granulomatous slack skin. Arch DermatoI1985;121:250-2. 18. Ackerman AB, F1axman BA. Granulomatous mycosis fungoides. Br J DermatoI1970;82:397-401.
CORRECTION
In the article "Aneurysm in the skin: Arterial fibromuscular dysplasia," by Kanzaki et a1., which appeared in the November 1992 Case Reports supplement, volume 27, number 5, part 2, the legends for Figures 2 and 3 on page 884 were transposed.