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Discordant Malignant Lymphoma Synchronous or Successive High-grade B Lymphoma Associated with Hodgkin#X2019:s Disease
Path. Res. Pract. 191,8-15 (1995)
Discordant Malignant Lymphoma Synchronous or Successive High-grade B Lymphoma Associated with Hodgkin's Disease A Clinico Pathologic and Immunophenotypic Study of 4 Cases D. Damotte1, A. Le Tourneau1, J. Audouin\ C. DuvaF, F. Martin-Bastenaire3 , O. Villain4, A. Delobelle-Deroide 4, and J. Diebold 1 IService Central "Jacques-Delarue" d'Anatomie et de Cytologie Pathologiques, Hotel-Dieu.; 2Laboratoire d'Anatomie et de Cytologie Pathologiques, Centre Henri-8ecquerel, Rouen; 3Centre d'Anatomie et de Cytologie Pathologiques, Orleans; 4Service d'Anatomie et de Cytologie Pathologiques, Centre Oscar Lambert, Lille, France.
Summary We report in 4 patients the rare association of Hodgkin's disease and high grade B malignant lymphoma. In 2 cases, both tumours were disclosed at the same time but in different tissues from the same region. In the 2 other patients, the second tumour was found 11 months and 12 months after the first respectively. In all cases Hodgkin's disease was of the nodular sclerosing type, the tumour cells expressing CD 30 and CD 15. The high grade lymphomas were of the polymorphic centroblastic (large non cleaved) type and expressed the B markers. One (case 4) was secondary to a follicular lymphoma. In 2 cases (2 and 4) the search for a latent EBV infection was negative in both tumours. In case 1, only the Reed-Sternberg cells were positive with both techniques. Such an association is different from so-called composite lymphomas, and can be called "discordant lymphoma". Different related conditions are discussed. This association is distinct from lymphomas or Hodgkin's disease complicating the treatment of Hodgkin's disease or malignant lymphomas.
Introduction The association of a high grade B non-Hodgkin's lymphoma (NHL) and a Hodgkin's disease (HD) has been already reported by many authors 1, 2, 3, 8, 9,10,11,
We report 4 cases of such an association, both tumours being discovered simultaneously or successively, in a short period of time.
13,14,15,17,18,19,20,23,25,29,33,35.
This association could be a chance occurrence, a bimorphic expression of the same tumour, the consequence of the same oncogenic factor, a complication of the therapy or what is known as composite lympho-
ma (eL), or discordant lymphoma (DL). 0344-0338/95/0191-0008$3.50/0
Materials and Methods All cases of associated HD and NHL studied in our department between 1986 and 1991 were reviewed. We excluded the association of HD and anaplastic large cell lymphoma and of high-grade B cell lymphoma occurring in nodular paragranulo© 1995 by Gustav Fischer Verlag, Stuttgart
High Grade B Lymphoma and Hodgkin's Disease . 9 rna. Four cases associating HD and NHL were found. All were sent to our department for diagnostic confirmation and advice. Paraffin-embedded sections were stained using the hematoxilin and eosin, Giemsa, PAS and Gordon-Sweet's silver impregnation techniques. Immunohistochemical staining was performed using the avidin-biotin complex immunoperoxidase technique. The antibodies used were: CD15 (Becton-Dickinson, Paris, France), MB2 (Biolyon, Lyon, France), UCHLl (CD45Ro), CD30, L26 (CD20), and polyclonal CD3 (Dakopatts, Paris, France). In addition, the presence of a latent Epstein-Barr virus (EBV) infection was explored in both tumours in case 1, 2 and 4. The expression for LMP-l was studied on paraffin sections by immunohistochemistry using monoclonal antibodies Cl-C4 (Dakopatts) with an APAAP method. In situ hybridization on formalin-fixed paraffin-embedded tissue was performed in these 3 cases with fluorescein-labelled EBER-l oligonucleotidic probe (Dakopatts) detected by a biotynilated-anti-FITC monoclonal antibody, alkaline phosphatase streptavidin and NBT-BCIP. HD was classified according to criteria specified within the Rye system based on the proposal by Lukes et all!, 34 with some modifications used in France s,6 and according to the BNLI classification22 .
NHL were classified according to the updated Kiel classification 30 and translated into the Working Formulation equivalents (WF)24.
Clinical Data
Case 1 A 20-year-old man was admitted for a transient episode of unconsciousness. He had noticed a cough during the last several months. Physical examination was normal. There were no particular laboratory findings. X-ray and CT scan of the chest revealed a voluminous mediastinal tumour involving the lung and the pleura, suggesting the development of a thymoma. Tumor removal was impossible. Only a biopsy of the mass was performed. Histopathologic study disclosed a diffuse tumour infiltrating the lung parenchyma and the mediastinal pleura. The diffuse proliferation was made of large cells (Fig. lA) with the morphology of centroblasts (large non-cleaved cells) and immunoblasts. There was a fibrous background with some reactive histiocytes and small lymphocytes. The diagnosis
Fig. 1. Case 1. A: Polymorphic centro blastic (large non cleaved) malignant lymphoma of the mediastinum (Giemsa, G = 300 X). - B: Nodular sclerosing Hodgkin's disease of the thymus (Hematoxylin-eosin, G = 150 X). Inset: Reed-Sternberg cell expressing CD 15. The same positivity was disclosed for CD 30 (Immunoperoxidase, G = 630 X).
10 . D. Damotte et al.
was high grade B cell malignant lymphoma of the mediastinum with lung involvement classified as polymorphic centro blastic according to the updated Kiel classification, group G (large non-cleaved cell) in the WE By contrast, the thymus was infiltrated and destroyed by sheets of lymphocytes, eosinophils and plasma cells surrounded by large annular fibrotic bands. In the nodules, Reed-Sternberg cells of the lacunar type or with a typical morphology were found (Fig. lB). The final diagnosis was thymic HD without extra-thymic extension, nodular sclerosing type (type 2 of the Rye classification) subtype 3 (in the French modified classification), grade 1 of the BNLI classification. The clinical course was short, the patient dying 2 months later due to neurologic complications. No autopsy could be performed.
Case 2 A 25-year-old man was admitted for mediastinal compression. Physical examination found bilateral axillar and subclavicular lymph nodes. X-Ray and CT scan revealed voluminous mediastinal lymph nodes.
A biopsy of a left supraclavicular lymph-node was performed. Histopathologic study found a typical pattern of HD, nodular sclerosing type (Fig. 2A) (type 2 of the Rye classification) subtype 4 sarcoma (in the French modified classification), corresponding to grade 2 of the BNLl classification. Lymphography, abdominal CT scan and bone marrow biopsy were normal. The patient received 6 cycles chemotherapy (EVBP type) and sub-diaphragmatic radiotherapy (40 grays). Eleven months after the diagnosis, 4 months after the end of the treatment, the patient complained of pain in the right hypochondrium with vomiting. CT scan showed bilateral para-aortic and coeliac adenopathies, and renal involvement. An exploratory laparotomy was performed with biopsies of the para-aortic lymph-node and the liver. The lymph-node was infiltrated by a diffuse proliferation of large cells (Fig. 2B), with the morphology of centro blasts (large non cleaved cells). The diagnosis was high grade B malignant lymphoma, polymorphic centroblastic type according to the updated Kiel classification, group G (large non cleaved cell) in the WE The liver was not involved.
Fig. 2. Case 2. A: Supraclavicular lymph node: nodular sclerosing Hodgkin's disease with a high content of tumour cells (Hematoxylin-eosin, G = 120 X), Inset: lacunar cell (Hematoxylin-eosine, G = 695 X). - B: Para-aortic lymph node: polymorphic centroblastic (large non cleaved) malignant lymphoma (Giemsa, G = 200 X).
High Grade B Lymphoma and Hodgkin's Disease . 11
The patient again received polychemotherapy (ACVBP and IVAM). A bone marrow autograft was performed after BEAM treatment. One year after the diagnosis of centro blastic lymphoma and 6 months after the bone marrow graft, relapse occurred in the mediastinum and the abdomen. He was again treated wit~ P?lychemotherapy. The patient is still in complete remiSSlOn. Case 3
An 85-year-old man was admitted for the exploration of a tumorous tonsil. Physical examination disclosed a left cervical lymph node. The tonsil was biopsied. Histopathologic study revealed a diffuse infiltration of the tonsil by large cells with the morphology of centroblasts (large non cleaved cell) or immunoblasts (Fig. 3A). The diagnosis was high grade B malignant lymphoma, polymorphic centro blastic type in the updated Kiel classification, group G in the WE The patient received only chemotherapy. At the end of the treatment, he presented a residual left spinal lymph node which was biopsied. Histopathologic study found a typical pattern of HD nodular sclerosing
type (type 2 of the Rye classification) (Fig. 3B), subtype 3 in the French modified classification, grade I in the BNLI classification. No information concerning the follow-up could be obtained. Case 4
A 40-year-old woman was admitted for appendicectomy. She noticed weakness and weight loss. Two months later she complained of abdominal pain. A colonoscopy disclosed a sigmoid compression by tumour masses. CT scan revealed caeliomesenteric lymphadenopathies and a retroperitoneal mass compressing the left ureter. A laparotomy was performed. An ileectomy and a sigmoidectomy were carried out together with a para-aortic lymph node biopsy. The tumour was located in the lymph node with extension to the mesenterium, sigmoid and ileon. Histopathologic study found (Fig. 4A) a HD of para-aortic lymph node with extension to the mesenterium, the ileon and the sigmoid, nodular sclerosing type (type 2 of the Rye classification) subtype in the French modified classification, grade 1 in the BNLI classification.
Fig. 3. Case 3. A: Tonsil: polymorphic centro blastic (large non-cleaved) malignant lymphoma (Giemsa, G = 350 X). - B: Left spinal lymph node: nodular sclerosing Hodgkin's disease (Giemsa = 120 X).
12 . D. Damotte et al.
The patient received chemotherapy and abdominal radiotherapy. The final results were excellent with no more residual tumour mass at CT scan of the chest and abdomen. Twelve months after the initial diagnosis, a sub-maxillary lymph node was disclosed. Histopathologic study of the biopsy recognized a follicular lymphoma with an association of small cleaved cells and large cells with round nuclei and 2-3 small sized nucleoli. In some follicles the large cells represented more than 50 % of the follicle population (Fig. 4B). The diagnosis was low grade centroblasticlcentrocytic follicular lymphoma with an evolution to a high grade malignant lymphoma polymorphic centroblastic type according to the updated Kiel classification, group G in the WF secondary. Cytogenetic study revealed a t(14-18) translocation. At that time, CT-scan of the thorax and abdomen were normal and no treatment was given. At present, 31 months after the diagnosis of the B lymphoma, the patient is well.
Results An association of HD and high-grade B ML was observed in 4 patients. In cases 1 and 3 both tumours were disclosed at the same time but in different tissues from the same region: HD of the thymus with high-grade B cell ML of the mediastinum in case 1, HD of a cervical adenopathy with high-grade B cell ML of the tonsil in case 3. In the 2 other cases the 2 tumours were found successively, also in the same region but not in the same organ. In case 2, HD was observed in retroperitoneal lymph nodes and the high-grade B ML in other retroperitoneal adenopathies. In case 4, the initial HD involvement was disclosed in mediastinal, axillary and supraclavicular adenopathies while the high grade B ML infiltrated a sub-maxillary lymph node. In all the cases, the HD belonged to the nodular sclerosing type and the NHL were of B cell origin with the morphology of a polymorphic centro blastic type (large non-cleaved cell). One was secondary to a previous low grade centroblastic-centrocytic follicular lymphoma. Both tumours were present in the same anatomical
Fig. 4. Case 4. A: Paracolic lymph node: nodular sclerosing Hodgkin's disease (Hematoxylin-eosin, G = 140 X). Inset: lacunar cell (Hematoxylin-eosin, G = 695 X). - B: Sub maxillary lymph node: polymorphic centroblastic (large non-cleaved malignant lymphoma secondary to follicular lymphoma (Hematoxylin-eosin, G = 350 X).
High Grade B Lymphoma and Hodgkin's Disease . 13
region but were never admixed in the same tissue or organ. Immunohistochemistry confirmed on the one hand the diagnosis of HD and B cell high-grade ML and, on the other, the absence of a admixture of both tumours in the same organ. In all the cases, the Reed-Sternberg cells of the HD expressed CD 30 and CD 15 and were negative for the B (MB 2, CD 20) and T (CD 45 RO, CD 3) markers. In the 3 cases studied (1, 2 and 4) the Reed-Sternberg cells were positive for LMP-1 and EBER -1 only in case 1. In all the centro blastic lymphomas the tumour cells were negative for CD 30, CD 15 and the T markers but expressed CD 20 and MB 2. In the 3 cases tested, LMP-1 and EBER-1 were negative. Discussion We report the unusual association in 4 patients of HD and high grade B cell ML occurring in different tissues in the same region but without admixture of both tumours. In 2 cases (n° 1 and 3), both tumours were found simultaneously. In the 2 other cases, the high-grade B cell ML was disclosed a short time after the treatment of the HD (11 months in case 2, 12 months in case 4). None of these cases can be regarded as a composite lymphoma. This entity described by Custer et al 6 was defined as the occurrence of 2 different and well-delineated NHL in the same lymph node or organ. This initial concept was later widened by Kim et aP7 who reported the first case of composite lymphoma constituted by the association of HD and NHL. The incidence of true composite ML seems to be very low. The review of the literature made by Kim et aP7 collected 20 cases, 8 of which concerned the association of HD and NHL. Some isolated cases have been reported since3, 9, 10, 13, 14, 15,23,25,26,29,31,33,35. In 1979, Van den Tweel et aP5 criticized this concept. For these authors, true composite lymphoma are extremely rare and the majority of reported cases could be interpreted as the occurrence of 2 different morphologic expressions of the same tumour cell clone. In fact, the cases we report are also different from 2 other conditions showing an association of HD and NHL. One concerns the association, simultaneously or successively, of HD lymphocyte predominance type and high-grade B celllymphoma4, 12,27,31. This condition, quite different from our cases, is now interpreted as a primary B cell lymphoma resembling HD with a possible evolution to high-grade B cell lymphoma 4. This entity, called nodular paragranuloma 12,27, is consistent with the interpretation of Van den Tweel et aP5. The other condition concerns the succession of HD and anaplastic large cell ML, which can be interpreted as the development of a high grade ML in the course of HD5,7. This association could also perhaps be interpreted as different expressions of the proliferation of a same clone of tumour cells 25 .
How can we interpret our cases? In 2 of them, the high grade B ML was disclosed after the treatment of HD. It is known that the risk of NHL in patients treated for HD is significantly elevated 36 , from 0.7 to 5.9 % depending on the studyl,35 and 4 % for Krikorian 20 . By definition, a NHL corresponding to a secondary malignancy induced by the association of radiotherapy and chemotherapy appears after an interval ranging from 2 to 10 years 1, 5,8,13,15,19,20,35. In the series of Zarate-Osorna 36 , the average interval in 14 patients, from the time of HD diagnosis to the time of NHL diagnosis was 11 years, 4 months (range 11 months to 28 years). In both our patients, the interval was only 11 and 12 months and in fact, the tumours were noted at the initial staging. Heinz et al13 did not accept cases in which the interval between the discovery of both diseases was less than 12 months. These authors avoided including in this group, patients with parallel development of HD and NHL, such as ours. The interval between the end of the chemotherapy and the development of the non-Hodgkin's lymphoma is too short in our cases to interprete such occurrence as a consequence of the treatment. The reverse condition, constituted by the occurrence of HD following NHL was also described by Travis et al 33 , with an expected ratio of 2.68 %. In this report, the median interval between both malignancies was 65 months, ranging from 11 to 137 months. Zarate-Osorna et aP7 reported 9 cases of such a condition and the median interval was 5 years (range 2-12 years). This association was also different from our cases. Finally, the association described in our 4 patients did not correspond to composite lymphoma. It could be defined as discordant lymphoma, the occurrence of 2 different lymphomas in different organs 25 . This condition can be interpreted according to 3 hypotheses. The 2 types of lymphoid malignancy can occur in the same patient only by chance, each being frequent in patients of that age group. This hypothesis was proposed by Rappaport et aIl8 and approved by Toner et ap2. The 2nd hypothesis which can be evoked concerns the role of decreased immunosurveillance in patients with HD or NHL allowing the emergence of another tumour 36 ,37. The last hypothesis could be that both malignancies were the result of the same oncogenic stimulation. EBV, for example, seems to be frequently associated with tumour cell proliferation in HD and in some highgrade B cell NHL. Recently Garner et apo reported a case of simultaneous occurrence of HD and NHL in an HIV-positive patient. They demonstrated the presence of EBV genoma by in situ hybridization in the Reed-Sternberg's cells and in the tumour cells of the high grade B cell NHL 10. Khan et al stressed in a recent letter to the editor 16 that they were able to demonstrate the presence of EBV at the cellular level in NHL, arising after treatment for HD, with both components being EBV-positive. In 2 of our cases, we were unable to demonstrate the expression of LMP-1 by immunohisto-
14 . D. Damotte et al.
chemistry and the presence of EBER-1 by in situ hybridization in the 2 types of tumour. In case 1, only the tumour cells of HD were positive. Finally, pathologists and oncologists should be aware enough of the possibility of HD and NHL occuring simultaneously in the same patient for misdiagnosis to be avoided. The significance should be discussed after comparison with the clinical data. Such cases should be carefully studied in the future with molecular biology and cytogenetic. Acknowledgements We thank Mr. Maurice Wolfelsperger for providing the photographs.
References 1 Bennett MH, Mac Lennan KA, Hudson GV and Hudson BV (1991) British national lymphoma investigation. NonHodgkin's lymphoma arising in patients treated for Hodgkin's disease in the BNLI: a 20-year experience. Ann Oncol 2: (SuppI2), 83-92 2 Carroto A, Filippa D and Koziner B (1987) Hodgkin's Disease after treatment of Non-Hodgkin's Lymphoma. Cancer 60: 887-896 3 Casey IT, Cousar JB, Mangum M, William ME, Lee T, Greer JP and Collins RD (1990) Monomorphic lymphomas arising in patients with Hodgkin's disease. Correlation of morphologic, immunophenotypic and molecular genetic findings in 12 cases. Amer J Pathol136: 81-94 4 Chitta I SM, Alard C, Rossi JF, Al Saati T, Le Tourneau A, Diebold J and Delsol G (1990) Further phenotypic evidence that nodular, Iymphocytepredominant Hodgkin's disease is a large B-cell lymphoma in evolution. Amer J Surg Pathol14: 1024-1035 5 Culine S, Henry-Amar M and Diebold] (1989) Relationship of histological subtypes to prognosis in early stage Hodgkin's disease: a review of 312 cases in a controlled clinical trial. EuropJ Cancer Clin Oncol 25: 551-556 6 Custer P (1954) Pitfalls in the diagnosis of lymphoma and leukemia from the pathologist's point of view. Proceeding of the second National Cancer Conference. New York. Amer Cancer Soc 554-557 7 Diebold J and Audouin J (1989) Maladie de Hodgkin. Une ou plusieurs maladies? Ann Pathol 9: 84-91 8 Fisher IR (1983) Non Hodgkin's Lymphoma after treatment of Hodgkin's disease. Arch Inter Medicine 142: 427 9 Gonzalez CL, Medeiros LJ and Jaffe ES (1991) Composite Lymphoma: a clinicopathologic analysis of nine patients with Hodgkin's disease and B-cell Non Hodgkin's Lymphoma. Amer J Clin Pathol 96: 81- 89 10 Guarner J, Del Rio C, Hendine Land Unge ER (1990) Composite Hodgkin's and Non-Hodgkin's Lymphoma in a patient with acquired immune deficiency syndrome. In situ demonstration of EBV. Cancer 66: 796 - 800 11 Hansmann ML, Fellbaum C, Hui PK and Lennert K (1989) Morphological and immunohistochemical investigation of Non-Hodgkin's lymphoma combined with Hodgkin's Disease. Histopathol 15: 35 - 48
12 Hansmann ML, Stein H, Fellbaum C, Hui PK, Parwaresch MR and Lennert K (1989) Nodular paragranuloma can transform into high-grade malignant lymphoma of B type. Hum Pathol 20: 1169-1175 13 Heinz R and Hanak H (1984) Non-Hodgkin's lymphoma following Hodgkin's disease. A case report. Blut 49: 353357 14 Horschowski N, Sanity D, Favre Rand Carcassonne Y (1980) A propos d'un cas de Iymphome composite: revue de la litterature. Ann Anat Pathol 25: 307-315 15 Jaquillat C, Khayat D, Desprez-Curely JP, Weil M, Brocheriou C, Auclerc G, Chamseddine and Bernard] (1984) Non-Hodgkin's lymphoma occurring after Hodgkin's disease: four new cases and a review of the literature. Cancer 53: 459-462 16 Khan G, Norton AJ and Slavin G (1993) Presence of Epstein-Barr virus in non-Hodkin's lymphomas arising in patients treated for Hodgkin's disease. Internat J Cancer 53: 529-530 17 Kim H and Dorfman RF (1974) Morphological studies of 84 untreated patients subjected to laparotomy for the staging of Non-Hodgkin's lymphomas. Cancer 33: 657-674 18 Kim H, Hendrickson MR and Dorfman RF (1977) Composite lymphoma. Cancer 40: 959-976 19 Kim H, Bedetti CD and Boggs DR (1980) The development of non-Hodgkin's lymphoma following therapy for Hodgkin's disease. Cancer 46: 2596-2602 20 Krikorian JG, Burke JS, Rosenberg SA and Kaplan HS (1979) Occurrence of non-Hodgkin's lymphoma after therapy for Hodgkin's disease. N Eng J Med 300: 452-458 21 Lukes RJ and Butler JJ (1966) The pathology and nomenclature of Hodgkin's disease. Cancer Res 26: 1063 -1081 22 Mc Lennan KA, Bennett MH, Tu A, Vaughan Hudson B, Easteruing J, Vaughan Hudson G and Jelliffe AM (1989) Relationship of histopathologic features to survival and relapse in nodular sclerosing Hodgkin's disease. A study of 1659 patients. Cancer 64: 1686-1693 23 Mittal BB and Nalesnik M (1986) Composite lymphoma (Hodgkin's and non-Hodgkin's) of the spleen in a previously untreated patient. Acta Haematol 76: 29-32 24 National Cancer Institute sponsored study of classification of Non-Hodgkin's Lymphoma (1982) Summary and description of WF for clinical usage. Cancer 49: 2112-2135 25 Paulli M, Rosso R, Kindl S, Boveri E, Sirchi M, De Medici A, Invernizzi Rand Magrani U (1992) Nodular sclerosing Hodgkin's disease and large cell lymphoma. Immunophenotypic characterization of a composite case. Virch Arch A Pathol Anat 421: 271-275 26 Po on M, Flint A and Miles GL (1980) Composite lymphoma. Cancer 46: 1676-1682 27 Poppema S, Timens Wand Visser L (1985) Nodular lymphocyte predominance type of Hodgkin's disease is a B cell Iymfhoma. Adv in Exp Med Bioi 186: 963-969 2 Rappaport H, Winter H and Hicks WJ (1956) Follicular lymphoma, a revaluation of its position in the scheme of malignant lymphoma based on a survey of 253 cases. Cancer 9: 792-821 29 Salter SR, Sheenhan T, Krajewski AS and Ludlam CA (1987) Immunohistological diagnosis of a case of composite lymphoma. Brit J Haematol 66: 479-482 30 Stansfeld AG, Diebold J, Noel H, Kapanci Y, Rilke F, Kelennyi G, Sundstrom C, Lennert K and Van Unnik JA (1988) Updated Kiel classification for lymphomas. Lancet 1: 292-293 31 Sundeen J, Cossman J and Jaffe ES (1988) Lymphocyte predominance Hodgkin's disease, nodular subtype with coex-
High Grade B Lymphoma and Hodgkin's disease . 15 istent "large cell lymphoma": histological progression or composite malignancy? Amer J Surg Pathol12: 599-606 32 Toner GC, Sinclair A, Sutherland RC and Scharwarz MA (1986) Composite lymphoma. Amer J Clin Pathol 86: 375-378 33 Tra vis LB, Gonzalez CL, Hankey BF and Jaffe ES (1992) Hodgkin's disease following non-Hodgkin's lymphoma. Cancer 69: 2337 -2342 34 Urba WJ and Longo DL (1992) Hodgkin's disease. N En~ J Med 5: 678-687 5 Van den Tweel JG, Lukes RJ and Taylor CR (1979) Pathophysiology of lymphocyte transformation. A study of so called composite lymphoma. Amer J Clin Pathol 71: 509-520
36 Van Leeuwen FE, Sommers Rand Taal BG (1989) Increased risk of lung cancer, non-Hodgkin's lymphoma and leukemia following Hodgkin's disease. J Clin Oncol 7: 1046-1058 37 Zarate Osorno A, Jeffrey Medeiros L, Longo DL and Jaffe ES (1992) Non-Hodgkin's lymphomas arising in patients successfully treated for Hodgkin's disease. A clinical, histologic, and immunophenotypic study of 14 cases. Amer J Surg Pathol16: 885-895 38 Zarate-Osorno A, Jeffrey-Medeiros L, Kingma DW, Longo DL and Jaffe ES (1993) Hodgkin's disease following non-Hodgkin's lymphoma. A clinicopathologic and immunophenotypic study of 9 cases. Amer J Surg Pathol17: 123 -132
Received February 23, 1994 . Accepted in revised form September 12, 1994
Key words: High grade B lymphoma - Hodgkin's disease - Composite lymphoma - Discordant lymphoma Pro J. Diebold, Service Central "Jacques-Delarue" d' Anatomie et de Cytologie Pathologiques, Hotel-Dieu, 1, Place du Parvis Notre-Dame, F. 75181 Paris Cedex 04, TeL 33 (1) 42348282, Fax: 33 (1) 42348078
Discordant Malignant Lymphoma Synchronous or Successive High-grade B Lymphoma Associated with Hodgkin's Disease A Clinico Pathologic and Immunophenotypic Study of 4 Cases D. Damotte1, A. Le Tourneau1, J. Audouin\ C. DuvaF, F. Martin-Bastenaire3 , O. Villain4, A. Delobelle-Deroide 4, and J. Diebold 1 IService Central "Jacques-Delarue" d'Anatomie et de Cytologie Pathologiques, Hotel-Dieu.; 2Laboratoire d'Anatomie et de Cytologie Pathologiques, Centre Henri-8ecquerel, Rouen; 3Centre d'Anatomie et de Cytologie Pathologiques, Orleans; 4Service d'Anatomie et de Cytologie Pathologiques, Centre Oscar Lambert, Lille, France.
Summary We report in 4 patients the rare association of Hodgkin's disease and high grade B malignant lymphoma. In 2 cases, both tumours were disclosed at the same time but in different tissues from the same region. In the 2 other patients, the second tumour was found 11 months and 12 months after the first respectively. In all cases Hodgkin's disease was of the nodular sclerosing type, the tumour cells expressing CD 30 and CD 15. The high grade lymphomas were of the polymorphic centroblastic (large non cleaved) type and expressed the B markers. One (case 4) was secondary to a follicular lymphoma. In 2 cases (2 and 4) the search for a latent EBV infection was negative in both tumours. In case 1, only the Reed-Sternberg cells were positive with both techniques. Such an association is different from so-called composite lymphomas, and can be called "discordant lymphoma". Different related conditions are discussed. This association is distinct from lymphomas or Hodgkin's disease complicating the treatment of Hodgkin's disease or malignant lymphomas.
Introduction The association of a high grade B non-Hodgkin's lymphoma (NHL) and a Hodgkin's disease (HD) has been already reported by many authors 1, 2, 3, 8, 9,10,11,
We report 4 cases of such an association, both tumours being discovered simultaneously or successively, in a short period of time.
13,14,15,17,18,19,20,23,25,29,33,35.
This association could be a chance occurrence, a bimorphic expression of the same tumour, the consequence of the same oncogenic factor, a complication of the therapy or what is known as composite lympho-
ma (eL), or discordant lymphoma (DL). 0344-0338/95/0191-0008$3.50/0
Materials and Methods All cases of associated HD and NHL studied in our department between 1986 and 1991 were reviewed. We excluded the association of HD and anaplastic large cell lymphoma and of high-grade B cell lymphoma occurring in nodular paragranulo© 1995 by Gustav Fischer Verlag, Stuttgart
High Grade B Lymphoma and Hodgkin's Disease . 9 rna. Four cases associating HD and NHL were found. All were sent to our department for diagnostic confirmation and advice. Paraffin-embedded sections were stained using the hematoxilin and eosin, Giemsa, PAS and Gordon-Sweet's silver impregnation techniques. Immunohistochemical staining was performed using the avidin-biotin complex immunoperoxidase technique. The antibodies used were: CD15 (Becton-Dickinson, Paris, France), MB2 (Biolyon, Lyon, France), UCHLl (CD45Ro), CD30, L26 (CD20), and polyclonal CD3 (Dakopatts, Paris, France). In addition, the presence of a latent Epstein-Barr virus (EBV) infection was explored in both tumours in case 1, 2 and 4. The expression for LMP-l was studied on paraffin sections by immunohistochemistry using monoclonal antibodies Cl-C4 (Dakopatts) with an APAAP method. In situ hybridization on formalin-fixed paraffin-embedded tissue was performed in these 3 cases with fluorescein-labelled EBER-l oligonucleotidic probe (Dakopatts) detected by a biotynilated-anti-FITC monoclonal antibody, alkaline phosphatase streptavidin and NBT-BCIP. HD was classified according to criteria specified within the Rye system based on the proposal by Lukes et all!, 34 with some modifications used in France s,6 and according to the BNLI classification22 .
NHL were classified according to the updated Kiel classification 30 and translated into the Working Formulation equivalents (WF)24.
Clinical Data
Case 1 A 20-year-old man was admitted for a transient episode of unconsciousness. He had noticed a cough during the last several months. Physical examination was normal. There were no particular laboratory findings. X-ray and CT scan of the chest revealed a voluminous mediastinal tumour involving the lung and the pleura, suggesting the development of a thymoma. Tumor removal was impossible. Only a biopsy of the mass was performed. Histopathologic study disclosed a diffuse tumour infiltrating the lung parenchyma and the mediastinal pleura. The diffuse proliferation was made of large cells (Fig. lA) with the morphology of centroblasts (large non-cleaved cells) and immunoblasts. There was a fibrous background with some reactive histiocytes and small lymphocytes. The diagnosis
Fig. 1. Case 1. A: Polymorphic centro blastic (large non cleaved) malignant lymphoma of the mediastinum (Giemsa, G = 300 X). - B: Nodular sclerosing Hodgkin's disease of the thymus (Hematoxylin-eosin, G = 150 X). Inset: Reed-Sternberg cell expressing CD 15. The same positivity was disclosed for CD 30 (Immunoperoxidase, G = 630 X).
10 . D. Damotte et al.
was high grade B cell malignant lymphoma of the mediastinum with lung involvement classified as polymorphic centro blastic according to the updated Kiel classification, group G (large non-cleaved cell) in the WE By contrast, the thymus was infiltrated and destroyed by sheets of lymphocytes, eosinophils and plasma cells surrounded by large annular fibrotic bands. In the nodules, Reed-Sternberg cells of the lacunar type or with a typical morphology were found (Fig. lB). The final diagnosis was thymic HD without extra-thymic extension, nodular sclerosing type (type 2 of the Rye classification) subtype 3 (in the French modified classification), grade 1 of the BNLI classification. The clinical course was short, the patient dying 2 months later due to neurologic complications. No autopsy could be performed.
Case 2 A 25-year-old man was admitted for mediastinal compression. Physical examination found bilateral axillar and subclavicular lymph nodes. X-Ray and CT scan revealed voluminous mediastinal lymph nodes.
A biopsy of a left supraclavicular lymph-node was performed. Histopathologic study found a typical pattern of HD, nodular sclerosing type (Fig. 2A) (type 2 of the Rye classification) subtype 4 sarcoma (in the French modified classification), corresponding to grade 2 of the BNLl classification. Lymphography, abdominal CT scan and bone marrow biopsy were normal. The patient received 6 cycles chemotherapy (EVBP type) and sub-diaphragmatic radiotherapy (40 grays). Eleven months after the diagnosis, 4 months after the end of the treatment, the patient complained of pain in the right hypochondrium with vomiting. CT scan showed bilateral para-aortic and coeliac adenopathies, and renal involvement. An exploratory laparotomy was performed with biopsies of the para-aortic lymph-node and the liver. The lymph-node was infiltrated by a diffuse proliferation of large cells (Fig. 2B), with the morphology of centro blasts (large non cleaved cells). The diagnosis was high grade B malignant lymphoma, polymorphic centroblastic type according to the updated Kiel classification, group G (large non cleaved cell) in the WE The liver was not involved.
Fig. 2. Case 2. A: Supraclavicular lymph node: nodular sclerosing Hodgkin's disease with a high content of tumour cells (Hematoxylin-eosin, G = 120 X), Inset: lacunar cell (Hematoxylin-eosine, G = 695 X). - B: Para-aortic lymph node: polymorphic centroblastic (large non cleaved) malignant lymphoma (Giemsa, G = 200 X).
High Grade B Lymphoma and Hodgkin's Disease . 11
The patient again received polychemotherapy (ACVBP and IVAM). A bone marrow autograft was performed after BEAM treatment. One year after the diagnosis of centro blastic lymphoma and 6 months after the bone marrow graft, relapse occurred in the mediastinum and the abdomen. He was again treated wit~ P?lychemotherapy. The patient is still in complete remiSSlOn. Case 3
An 85-year-old man was admitted for the exploration of a tumorous tonsil. Physical examination disclosed a left cervical lymph node. The tonsil was biopsied. Histopathologic study revealed a diffuse infiltration of the tonsil by large cells with the morphology of centroblasts (large non cleaved cell) or immunoblasts (Fig. 3A). The diagnosis was high grade B malignant lymphoma, polymorphic centro blastic type in the updated Kiel classification, group G in the WE The patient received only chemotherapy. At the end of the treatment, he presented a residual left spinal lymph node which was biopsied. Histopathologic study found a typical pattern of HD nodular sclerosing
type (type 2 of the Rye classification) (Fig. 3B), subtype 3 in the French modified classification, grade I in the BNLI classification. No information concerning the follow-up could be obtained. Case 4
A 40-year-old woman was admitted for appendicectomy. She noticed weakness and weight loss. Two months later she complained of abdominal pain. A colonoscopy disclosed a sigmoid compression by tumour masses. CT scan revealed caeliomesenteric lymphadenopathies and a retroperitoneal mass compressing the left ureter. A laparotomy was performed. An ileectomy and a sigmoidectomy were carried out together with a para-aortic lymph node biopsy. The tumour was located in the lymph node with extension to the mesenterium, sigmoid and ileon. Histopathologic study found (Fig. 4A) a HD of para-aortic lymph node with extension to the mesenterium, the ileon and the sigmoid, nodular sclerosing type (type 2 of the Rye classification) subtype in the French modified classification, grade 1 in the BNLI classification.
Fig. 3. Case 3. A: Tonsil: polymorphic centro blastic (large non-cleaved) malignant lymphoma (Giemsa, G = 350 X). - B: Left spinal lymph node: nodular sclerosing Hodgkin's disease (Giemsa = 120 X).
12 . D. Damotte et al.
The patient received chemotherapy and abdominal radiotherapy. The final results were excellent with no more residual tumour mass at CT scan of the chest and abdomen. Twelve months after the initial diagnosis, a sub-maxillary lymph node was disclosed. Histopathologic study of the biopsy recognized a follicular lymphoma with an association of small cleaved cells and large cells with round nuclei and 2-3 small sized nucleoli. In some follicles the large cells represented more than 50 % of the follicle population (Fig. 4B). The diagnosis was low grade centroblasticlcentrocytic follicular lymphoma with an evolution to a high grade malignant lymphoma polymorphic centroblastic type according to the updated Kiel classification, group G in the WF secondary. Cytogenetic study revealed a t(14-18) translocation. At that time, CT-scan of the thorax and abdomen were normal and no treatment was given. At present, 31 months after the diagnosis of the B lymphoma, the patient is well.
Results An association of HD and high-grade B ML was observed in 4 patients. In cases 1 and 3 both tumours were disclosed at the same time but in different tissues from the same region: HD of the thymus with high-grade B cell ML of the mediastinum in case 1, HD of a cervical adenopathy with high-grade B cell ML of the tonsil in case 3. In the 2 other cases the 2 tumours were found successively, also in the same region but not in the same organ. In case 2, HD was observed in retroperitoneal lymph nodes and the high-grade B ML in other retroperitoneal adenopathies. In case 4, the initial HD involvement was disclosed in mediastinal, axillary and supraclavicular adenopathies while the high grade B ML infiltrated a sub-maxillary lymph node. In all the cases, the HD belonged to the nodular sclerosing type and the NHL were of B cell origin with the morphology of a polymorphic centro blastic type (large non-cleaved cell). One was secondary to a previous low grade centroblastic-centrocytic follicular lymphoma. Both tumours were present in the same anatomical
Fig. 4. Case 4. A: Paracolic lymph node: nodular sclerosing Hodgkin's disease (Hematoxylin-eosin, G = 140 X). Inset: lacunar cell (Hematoxylin-eosin, G = 695 X). - B: Sub maxillary lymph node: polymorphic centroblastic (large non-cleaved malignant lymphoma secondary to follicular lymphoma (Hematoxylin-eosin, G = 350 X).
High Grade B Lymphoma and Hodgkin's Disease . 13
region but were never admixed in the same tissue or organ. Immunohistochemistry confirmed on the one hand the diagnosis of HD and B cell high-grade ML and, on the other, the absence of a admixture of both tumours in the same organ. In all the cases, the Reed-Sternberg cells of the HD expressed CD 30 and CD 15 and were negative for the B (MB 2, CD 20) and T (CD 45 RO, CD 3) markers. In the 3 cases studied (1, 2 and 4) the Reed-Sternberg cells were positive for LMP-1 and EBER -1 only in case 1. In all the centro blastic lymphomas the tumour cells were negative for CD 30, CD 15 and the T markers but expressed CD 20 and MB 2. In the 3 cases tested, LMP-1 and EBER-1 were negative. Discussion We report the unusual association in 4 patients of HD and high grade B cell ML occurring in different tissues in the same region but without admixture of both tumours. In 2 cases (n° 1 and 3), both tumours were found simultaneously. In the 2 other cases, the high-grade B cell ML was disclosed a short time after the treatment of the HD (11 months in case 2, 12 months in case 4). None of these cases can be regarded as a composite lymphoma. This entity described by Custer et al 6 was defined as the occurrence of 2 different and well-delineated NHL in the same lymph node or organ. This initial concept was later widened by Kim et aP7 who reported the first case of composite lymphoma constituted by the association of HD and NHL. The incidence of true composite ML seems to be very low. The review of the literature made by Kim et aP7 collected 20 cases, 8 of which concerned the association of HD and NHL. Some isolated cases have been reported since3, 9, 10, 13, 14, 15,23,25,26,29,31,33,35. In 1979, Van den Tweel et aP5 criticized this concept. For these authors, true composite lymphoma are extremely rare and the majority of reported cases could be interpreted as the occurrence of 2 different morphologic expressions of the same tumour cell clone. In fact, the cases we report are also different from 2 other conditions showing an association of HD and NHL. One concerns the association, simultaneously or successively, of HD lymphocyte predominance type and high-grade B celllymphoma4, 12,27,31. This condition, quite different from our cases, is now interpreted as a primary B cell lymphoma resembling HD with a possible evolution to high-grade B cell lymphoma 4. This entity, called nodular paragranuloma 12,27, is consistent with the interpretation of Van den Tweel et aP5. The other condition concerns the succession of HD and anaplastic large cell ML, which can be interpreted as the development of a high grade ML in the course of HD5,7. This association could also perhaps be interpreted as different expressions of the proliferation of a same clone of tumour cells 25 .
How can we interpret our cases? In 2 of them, the high grade B ML was disclosed after the treatment of HD. It is known that the risk of NHL in patients treated for HD is significantly elevated 36 , from 0.7 to 5.9 % depending on the studyl,35 and 4 % for Krikorian 20 . By definition, a NHL corresponding to a secondary malignancy induced by the association of radiotherapy and chemotherapy appears after an interval ranging from 2 to 10 years 1, 5,8,13,15,19,20,35. In the series of Zarate-Osorna 36 , the average interval in 14 patients, from the time of HD diagnosis to the time of NHL diagnosis was 11 years, 4 months (range 11 months to 28 years). In both our patients, the interval was only 11 and 12 months and in fact, the tumours were noted at the initial staging. Heinz et al13 did not accept cases in which the interval between the discovery of both diseases was less than 12 months. These authors avoided including in this group, patients with parallel development of HD and NHL, such as ours. The interval between the end of the chemotherapy and the development of the non-Hodgkin's lymphoma is too short in our cases to interprete such occurrence as a consequence of the treatment. The reverse condition, constituted by the occurrence of HD following NHL was also described by Travis et al 33 , with an expected ratio of 2.68 %. In this report, the median interval between both malignancies was 65 months, ranging from 11 to 137 months. Zarate-Osorna et aP7 reported 9 cases of such a condition and the median interval was 5 years (range 2-12 years). This association was also different from our cases. Finally, the association described in our 4 patients did not correspond to composite lymphoma. It could be defined as discordant lymphoma, the occurrence of 2 different lymphomas in different organs 25 . This condition can be interpreted according to 3 hypotheses. The 2 types of lymphoid malignancy can occur in the same patient only by chance, each being frequent in patients of that age group. This hypothesis was proposed by Rappaport et aIl8 and approved by Toner et ap2. The 2nd hypothesis which can be evoked concerns the role of decreased immunosurveillance in patients with HD or NHL allowing the emergence of another tumour 36 ,37. The last hypothesis could be that both malignancies were the result of the same oncogenic stimulation. EBV, for example, seems to be frequently associated with tumour cell proliferation in HD and in some highgrade B cell NHL. Recently Garner et apo reported a case of simultaneous occurrence of HD and NHL in an HIV-positive patient. They demonstrated the presence of EBV genoma by in situ hybridization in the Reed-Sternberg's cells and in the tumour cells of the high grade B cell NHL 10. Khan et al stressed in a recent letter to the editor 16 that they were able to demonstrate the presence of EBV at the cellular level in NHL, arising after treatment for HD, with both components being EBV-positive. In 2 of our cases, we were unable to demonstrate the expression of LMP-1 by immunohisto-
14 . D. Damotte et al.
chemistry and the presence of EBER-1 by in situ hybridization in the 2 types of tumour. In case 1, only the tumour cells of HD were positive. Finally, pathologists and oncologists should be aware enough of the possibility of HD and NHL occuring simultaneously in the same patient for misdiagnosis to be avoided. The significance should be discussed after comparison with the clinical data. Such cases should be carefully studied in the future with molecular biology and cytogenetic. Acknowledgements We thank Mr. Maurice Wolfelsperger for providing the photographs.
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Received February 23, 1994 . Accepted in revised form September 12, 1994
Key words: High grade B lymphoma - Hodgkin's disease - Composite lymphoma - Discordant lymphoma Pro J. Diebold, Service Central "Jacques-Delarue" d' Anatomie et de Cytologie Pathologiques, Hotel-Dieu, 1, Place du Parvis Notre-Dame, F. 75181 Paris Cedex 04, TeL 33 (1) 42348282, Fax: 33 (1) 42348078