Pathology (1990), 22, pp. 173-174
LETTER TO THE EDITOR
Ki-1 POSITIVE ANAPLASTIC LARGE CELL LYMPHOMA The Ki- I monoclonal antibody raised against the Hodgkin’s disease derived cell line L428’ was initially thought to be a specific marker for Hodgkin’s disease Reed Sternberg cell. However, the Ki-l antigen (CD30) is also expressed o n a small population of activated T and B lymphocytes and a recently recognized subtype of non-Hodgkin’s lymphoma, the Ki-l positive anaplastic large cell lymphoma.’ We report a case of Ki-l positive lymphoma in order to draw attention to this recently described entity and highlight the lack of specificity of a single marker in the diagnosis of Hodgkin’s disease and other malignant lymphomas. Case history
A 25-year-old female presented with a five month history of a pyrexial illness associated with mild lethargy and intermittent swelling and tenderness of the right breast and right axilla. On examination she was febrile (temperature 38.2 “C), with erythema and induration of the right breast and non-tender lymphadenopathy involving the right axilla, right supraclavicular, and right anterior cervical regions. The liver and spleen were not palpable. A mammogram revealed mild lymphoedema of the right breast, and diffuse mesenteric, left para-aortic, and coeliac lymphadenopathy was documented o n abdomino-thoracic CT scanning. The ESR was elevated at 78 mm/hr with hemoglobin 80 g/L, leucocyte count 31.7 x 109/L (segmented neutrophil 27.6, lymphocytes 1.9) and platelets 787 x 109/L. The serum albumin was reduced at 29 g/L and hepatic function mildly disturbed with gamma glutamyl transpeptidase 333 units/L (0-50 u/L) and alkaline phosphatase 267 units/L (25-100 u/L). Examination of cerebrospinal fluid was normal. Biopsy of a right anterior cervical lymph node showed infiltration of sinusoidal and T cell zones of the lymph node by large, bizarre neoplastic cells, many of which were binucleate and resembled Reed-Sternberg cells on tissue imprint staining. These cells were negative for non-specific esterase.
(BerHZ)]. Many of these cells also expressed the IL-2 receptor (CD25) and HLA DR. Pan B and pan T markers were expressed in the residual T cell areas and B cell follicles respectively, however the neoplastic infiltration was negative for these markers. Bone marrow examination revealed infiltration by a similar population of cells, and fine needle aspiration of the right breast, although not diagnostic, demonstrated the presence of large mononucleate and binucleate cells consistent with tumor infiltration. The histo-pathological and cell marker appearances in this case are characteristic of Ki-l positive anaplastic large cell lymphoma. These tumors usually express the Reed-Sternberg cell marker Ki-l (CD30) but can clearly be distinguished from Hodgkin’s disease on morphological criteria, the co-expression of leucocyte common antigen (CD45). and by the proportion of cells that are positive for the Ki-I marker. In Hodgkin’s disease only a mincrity of cells express this antigen whilst there is extensive positivity of the tumor infiltrate in Ki-l l y m p h ~ m a . ~ In addition, these tumors may also express the epithelial membrane antigen and, as in this case, the activation markers CD25 (IL-2 receptor) and HLA DR (HLA Class I1 antigen).’ The majority of these lymphomas are of T cell origin on the basis of immunological, cytochemical and gene rearrangement ~ t u d i e s .A~ . ~ small number, however, have either a B cell or non B-non T (“null”)
Immunophenotypic analysis was performed o n frozen sections using an immuno-enzyme method (APAAP),3 and the result of the analyses is summarized in Table I. The region of tumor infiltration was strongly positive for the leucocyte common antigen (CD45) and the Ki-1 antigen (CD30), as shown in Fig. 1, [using the monoclonal antibody Ki-l
Antibody CD2 (TI I ) CD5 ( T I ) CD7 (T2) CD4 (T4) CD8 (T8) CD30 (BerH2) CD30 (RSCI) CD68 (EBM11) HLA DR CD45 (CMRFIZ) CD19 (HD37) CD22 (4KB128) CD25 (2A3)
Source
Tumor
DAKO DAKO DAKO DAKO DAKO DAKO DAKO DAKO DAKO D. Hart DAKO DAKO lmmunex
+’
-
-
-
+++ + + 2
+ ++ -
+
Non tumor
+ + + + + -
Scattered -
+
+ + -
Fig. I Expression of Ki-l antigen (BerH2) in right anterior cervical lymph node biopsy from patient (APAAP method x 160).
174
LETTER TO THE EDITOR
cell immunophenotype and this case would appear to fit the latter category. The clinical manifestations and prognosis of this recently described disorder are poorly defined. The diagnosis is often difficult and may be confused with malignant histiocytosis or anaplastic carcinoma. In general these lymphomas appear to occur more frequently in a younger age group, and a syndrome of skin infiltration and peripheral lymphadenopathy has recently been described in children and adolescents with Ki-1 positive lymphoma.6 The Ki-1 lymphoma is a high-grade lymphoma, and most cases to date have been treated with multiagent chemotherapy. As yet the longterm prognosis is not clear, and the importance of central nervous system prophylaxis unknown. However, with the increased availability of monoclonal antibodies to defined cell surface antigens and the recognition of these new subtypes of lymphoma, our knowledge of the manifestations, clinical behaviour and optimal treatment of this disorder will become clearer in the future. J . Browett,* J . Nelson, R . Thula and A. R. Varcoe Departments of Hematology and lmmunobiology School of Medicine University of Auckland Private Bag Auckland New Zealand
Pathology (1990), 22, July
References I . Schwab U, Stein H, Gerdes J et al. Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin’s disease and a subset of normal lymphoid cells. Nature 1982; 299: 65-7. 2. Stein H, Mason DY, Gerdes J et al. The expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 1985; 66: 848-58.
3. Cordell J L , Falini R, Erber WN et al. lmmunoenzymatic labelling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem 1984; 32: 219-29. 4. Suchi T , Lennert K, Tu L-Y et al. Histopathology and immunochemistry of peripheral T cell lymphomas: a proposal for their classification. J Clin Pathol 1987; 40: 995-1015.
5. Delsol G , Al Saati T, Gatter KC et al. Co-expression of epithelial membrane antigen (EMA), Ki-1, and interleukin-2 receptor by anaplastic large cell lymphomas. Am J Pathol 1988; 130: 59-70. 6. Kadin ME, Sako D, Berliner N et al. Childhood Ki-1 lymphoma presenting with skin lesions and peripheral lymphadenopathy. Blood 1986; 68: 1042-9. *Author for correspondence.
Prickly Heat Early one Red Sea morning, the nurse, who was rendered flabby by heat, crawled up on deck with the baby. She soon became ‘that ill’ that she had to stumble below, leaving the infant with a pyjama-clad officer of dragoons, who offered to take it. The child was not sleeping on this occasion, and indeed, as soon as the nurse had fled, it began t o howl dismally. The dragoon was much alarmed by this change in the habits of the infant. He was himself suffering at the time from prickly heat, and it struck him that the baby’s unhappiness might be due also to the same cause. So, with the assistance and advice of a mining expert, who was smoking in his pyjamas in the next chair, the baby was entirely undressed and rubbed with a’tobacco pouch. This treatment, although not in accord with the usages of the nursery, was immediately effectual, for when the still limp nurse returned to the deck, the baby was naked, but neither ashamed nor complaining. Sir Frederick Treves. The Other Side of the Lantern. Cassell & Co. 1904. p. 25.
LETTER TO THE EDITOR
Ki-1 POSITIVE ANAPLASTIC LARGE CELL LYMPHOMA The Ki- I monoclonal antibody raised against the Hodgkin’s disease derived cell line L428’ was initially thought to be a specific marker for Hodgkin’s disease Reed Sternberg cell. However, the Ki-l antigen (CD30) is also expressed o n a small population of activated T and B lymphocytes and a recently recognized subtype of non-Hodgkin’s lymphoma, the Ki-l positive anaplastic large cell lymphoma.’ We report a case of Ki-l positive lymphoma in order to draw attention to this recently described entity and highlight the lack of specificity of a single marker in the diagnosis of Hodgkin’s disease and other malignant lymphomas. Case history
A 25-year-old female presented with a five month history of a pyrexial illness associated with mild lethargy and intermittent swelling and tenderness of the right breast and right axilla. On examination she was febrile (temperature 38.2 “C), with erythema and induration of the right breast and non-tender lymphadenopathy involving the right axilla, right supraclavicular, and right anterior cervical regions. The liver and spleen were not palpable. A mammogram revealed mild lymphoedema of the right breast, and diffuse mesenteric, left para-aortic, and coeliac lymphadenopathy was documented o n abdomino-thoracic CT scanning. The ESR was elevated at 78 mm/hr with hemoglobin 80 g/L, leucocyte count 31.7 x 109/L (segmented neutrophil 27.6, lymphocytes 1.9) and platelets 787 x 109/L. The serum albumin was reduced at 29 g/L and hepatic function mildly disturbed with gamma glutamyl transpeptidase 333 units/L (0-50 u/L) and alkaline phosphatase 267 units/L (25-100 u/L). Examination of cerebrospinal fluid was normal. Biopsy of a right anterior cervical lymph node showed infiltration of sinusoidal and T cell zones of the lymph node by large, bizarre neoplastic cells, many of which were binucleate and resembled Reed-Sternberg cells on tissue imprint staining. These cells were negative for non-specific esterase.
(BerHZ)]. Many of these cells also expressed the IL-2 receptor (CD25) and HLA DR. Pan B and pan T markers were expressed in the residual T cell areas and B cell follicles respectively, however the neoplastic infiltration was negative for these markers. Bone marrow examination revealed infiltration by a similar population of cells, and fine needle aspiration of the right breast, although not diagnostic, demonstrated the presence of large mononucleate and binucleate cells consistent with tumor infiltration. The histo-pathological and cell marker appearances in this case are characteristic of Ki-l positive anaplastic large cell lymphoma. These tumors usually express the Reed-Sternberg cell marker Ki-l (CD30) but can clearly be distinguished from Hodgkin’s disease on morphological criteria, the co-expression of leucocyte common antigen (CD45). and by the proportion of cells that are positive for the Ki-I marker. In Hodgkin’s disease only a mincrity of cells express this antigen whilst there is extensive positivity of the tumor infiltrate in Ki-l l y m p h ~ m a . ~ In addition, these tumors may also express the epithelial membrane antigen and, as in this case, the activation markers CD25 (IL-2 receptor) and HLA DR (HLA Class I1 antigen).’ The majority of these lymphomas are of T cell origin on the basis of immunological, cytochemical and gene rearrangement ~ t u d i e s .A~ . ~ small number, however, have either a B cell or non B-non T (“null”)
Immunophenotypic analysis was performed o n frozen sections using an immuno-enzyme method (APAAP),3 and the result of the analyses is summarized in Table I. The region of tumor infiltration was strongly positive for the leucocyte common antigen (CD45) and the Ki-1 antigen (CD30), as shown in Fig. 1, [using the monoclonal antibody Ki-l
Antibody CD2 (TI I ) CD5 ( T I ) CD7 (T2) CD4 (T4) CD8 (T8) CD30 (BerH2) CD30 (RSCI) CD68 (EBM11) HLA DR CD45 (CMRFIZ) CD19 (HD37) CD22 (4KB128) CD25 (2A3)
Source
Tumor
DAKO DAKO DAKO DAKO DAKO DAKO DAKO DAKO DAKO D. Hart DAKO DAKO lmmunex
+’
-
-
-
+++ + + 2
+ ++ -
+
Non tumor
+ + + + + -
Scattered -
+
+ + -
Fig. I Expression of Ki-l antigen (BerH2) in right anterior cervical lymph node biopsy from patient (APAAP method x 160).
174
LETTER TO THE EDITOR
cell immunophenotype and this case would appear to fit the latter category. The clinical manifestations and prognosis of this recently described disorder are poorly defined. The diagnosis is often difficult and may be confused with malignant histiocytosis or anaplastic carcinoma. In general these lymphomas appear to occur more frequently in a younger age group, and a syndrome of skin infiltration and peripheral lymphadenopathy has recently been described in children and adolescents with Ki-1 positive lymphoma.6 The Ki-1 lymphoma is a high-grade lymphoma, and most cases to date have been treated with multiagent chemotherapy. As yet the longterm prognosis is not clear, and the importance of central nervous system prophylaxis unknown. However, with the increased availability of monoclonal antibodies to defined cell surface antigens and the recognition of these new subtypes of lymphoma, our knowledge of the manifestations, clinical behaviour and optimal treatment of this disorder will become clearer in the future. J . Browett,* J . Nelson, R . Thula and A. R. Varcoe Departments of Hematology and lmmunobiology School of Medicine University of Auckland Private Bag Auckland New Zealand
Pathology (1990), 22, July
References I . Schwab U, Stein H, Gerdes J et al. Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin’s disease and a subset of normal lymphoid cells. Nature 1982; 299: 65-7. 2. Stein H, Mason DY, Gerdes J et al. The expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 1985; 66: 848-58.
3. Cordell J L , Falini R, Erber WN et al. lmmunoenzymatic labelling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem 1984; 32: 219-29. 4. Suchi T , Lennert K, Tu L-Y et al. Histopathology and immunochemistry of peripheral T cell lymphomas: a proposal for their classification. J Clin Pathol 1987; 40: 995-1015.
5. Delsol G , Al Saati T, Gatter KC et al. Co-expression of epithelial membrane antigen (EMA), Ki-1, and interleukin-2 receptor by anaplastic large cell lymphomas. Am J Pathol 1988; 130: 59-70. 6. Kadin ME, Sako D, Berliner N et al. Childhood Ki-1 lymphoma presenting with skin lesions and peripheral lymphadenopathy. Blood 1986; 68: 1042-9. *Author for correspondence.
Prickly Heat Early one Red Sea morning, the nurse, who was rendered flabby by heat, crawled up on deck with the baby. She soon became ‘that ill’ that she had to stumble below, leaving the infant with a pyjama-clad officer of dragoons, who offered to take it. The child was not sleeping on this occasion, and indeed, as soon as the nurse had fled, it began t o howl dismally. The dragoon was much alarmed by this change in the habits of the infant. He was himself suffering at the time from prickly heat, and it struck him that the baby’s unhappiness might be due also to the same cause. So, with the assistance and advice of a mining expert, who was smoking in his pyjamas in the next chair, the baby was entirely undressed and rubbed with a’tobacco pouch. This treatment, although not in accord with the usages of the nursery, was immediately effectual, for when the still limp nurse returned to the deck, the baby was naked, but neither ashamed nor complaining. Sir Frederick Treves. The Other Side of the Lantern. Cassell & Co. 1904. p. 25.
