A Case Report of Down Syndrome and Centroblastic Lymphoma

Path. Res. Pract. 192, 1266 -1269 (1996)

A Case Report of Down Syndrome and Centroblastic Lymphoma D. Satge1, A. Le Tourneau 2 , J.-P. Verger3 , S. Lefort 4 , A. Geneix 5 , P. Malet 5 , J. Diebold 2 and M. Vekemans 6 1Laboratoire d'Anatomie Pathologique, CH Tulle, France; 2Laboratoire d'Anatomie Pathologique, H6telDieu Paris, France; 3Service de Pneumologie, Tulle, France; 4Service de Radiotherapie, Brive, France; 5Laboratoire de Cytogenetique, Faculte de Medecine Clermont-Ferrand, France; 6Laboratoire de Cytogenetique, H6pital Necker Paris, France

SUMMARY We describe a case of left cervical stage I centroblastic lymphoma in a 29-year old male patient with Down's syndrome due to a (14; 21) Robertsonian translocation. The disease presented as extensive lymph node necrosis leaving rare areas of tumor cells, accounting for the diagnostic difficulties. According to our review of the literature, lymphoma is one of the most common neoplasms in DS patients and may represent the second most common malignancy in this condition, far behind leukemia.

Introduction It is well known that Down's syndrome (DS) patients have a 20- to 30-fold increased risk of developing leukemia 17. The increased risk of developing other ty~es of malignancies has not been so clearly established . We report a case of lymphoma in a DS patient, and believe that the frequency of lymphoma in DS patients may well be underestimated. Case Report A 29-year old male patient with Down's syndrome due to a (14; 21) Robertsonian translocation was admitted complaining of fever and swelling of the left cervical lymph nodes. The patient was institutionalized and presented the classical features of DS and was profoundly autistic. The past medical history revealed the existence of cervical abscess at the age of four years, adenoidectomy at the age of nine years, and extraction of 13 teeth at the age of 27 years. He suffered from severe chronic sinusitis. He was treated 0344-0338/96/0192-1266$3.50/0

with Popericiazine (NeuleptiI R ) and Alimemazine (Theralene R ). At physical examination, lymph node swellings were palpated in the left cervical area. No abnormal abdominal mass was felt. Laboratory studies (Hb 12.2 mgl 100 ml, white blood cell count sOOO/mm 3 with 64% neutrophils, 24 % lymphocytes, 11 % monocytes, 1 % basophils) were within normal limits. Platelet count was 277000/mm 3 • Sedimentation rate was 106 and 150 after one and two hours, respectively. Immunoglobulin concentrations (IgA 7.11 gil, IgG 22.50 gil and IgM 0.85 gil) were within normal limits. LDH, Beta 2 globulin, as well as hepatic and renal function, were normal. Toxoplasmosis, infectious mononucleosis and HIV serologies were negative. Cervical lymph node biopsy showed a diffuse large cell malignant lymphoma with extensive necrosis (Fig. 1). The tumor cells were polymorphous and large, larger than lymphoblasts, with distinct nucleoli, and consisted of centroblasts and immunoblasts (Fig. 2). The centro blasts showed clear, round or more or less irregular nuclei, with 2 or 3 small to medium sized nucleoli, and thin basophilic cytoplasm. The immunoblasts were larger © 1996 by Gustav Fischer Verlag, Stuttgart

Down Syndrome and Lymphoma . 1267 Table 1. Cases published of Hodgkin diseases and non Hodgkin lymphomas in patients with Down syndrome Authors

Number of Cases

Sex

Age

Type

Treatment

Outcome

Holland et a1. 1962 Barber and Spiers 1964 Miller 1969

1 2 1

M NG M

44 Y
NG NG NG

DOD DOD DOD

Mc Cormick et a1. 1971

1

M

8Y

Hodgkin disease lymphomas lymphoblastic lymphoma Hodgkin disease

DOD

Oshimura et a1. 1981

1

M

17Y

Scholl et a1. 1982

4

NG

5-54 Y

NG

DOD

Baird and Sadovnick 1988 Lorenzana and Schorin 1989 Wang et a1. 1987 Narod et a1. 1991 Lorber et a1. 1992 Gurgeal et a1. 1993

1 1

NG M

NG 3 weeks

lymphoblastic lymphoma 1 Hodgkin disease 3 lymphomas Hodgkin disease T cell lymphoma

radiotherapy chemotherapy chemotherapy

NG chemotherapy

3 1 1

NG NG M

<15 Y 23 Y 6Y

lymphomas B cell lymphoma Hodgkin disease

Satge et a1. 1996

1

M

29 Y

polymorphic . centro blastic lymphoma

DOD Alive and well at 31 months NG NG Alive and well at 8 years DOD

NG NG radiotherapy chemotherapy no treatment

DOD

NG: not given - DOD: dead of disease

and had a large centrally situated nucleolus. These lymphoid cells strongly expressed CD20 (L26 Dakopatts) and slightly expressed BCL2. The diagnosis was high grade B cell malignant lymphoma, polymorphic centroblastic type according to the updated Kiel classification, group G (large non cleaved cell) in the Working Formulation. Abdominal ultrasonography and chest X-rays were normal. Given his severely autistic state, the usual treatment was excluded. Six months later, the patient developed asthenia and anorexia, but physical examination was within normal limits. Laboratory studies were, however, abnormal (10.7 g Hbl100 ml, platelet count 430000/mm 3 and LDH 375 UI/ml). Soon after, in March, he died quietly. An autopsy was not performed. Discussion Patients with Down's syndrome suffer from progressive immune deficiency15 leading to an excess of infectious diseases, responsible for an increased risk of death from infectious problems. In these patients an extensive lymph node necrosis could have led to a false diagnosis of infectious alterations, given the clinical history of chronic sinusitis. A careful examination revealed, in addition to the many dystrophic and necrotic leukocytes, small, limited areas of tumor cells. We report a case of Down's syndrome due to a Robertsonian translocation associated with a centro blastic lymphoma. A Robertsonian translocation is an abnormal fusion of two acrocentric chromosomes in the centromeric region. To our knowledge, only a

small number of lymphomas have been reported in patients with DS6, 10, 12, 16. However, according to epidemiological studies, lymphoma appears to be the second most common type of malignancy observed in patients with DS, well after leukemia (Tab. 1). In 1964, Barber and Spiers2 found 49 cases of leukemia, 2 cases of "lymphosarcoma" and one case of another cancer, in a series of 52 DS children who died before the age of 10 from a malignant disease. They estimated that the frequency of lymphosarcoma death rate for trisomy 21 is about eight times higher than normal. Recently, Narod et al. 14, in an incidence study of the British National Registry on Childhood Tumors, found 135 DS cases with 131 leukemias, 3 lymphomas, 2 gliomas, 1 testicular teratoma and 1 fibrosarcoma. In the largest study on causes of mortality in DS, Scholl et al. 20 found 44 malignancies, including four lymphomas. There was an excess of solid hematopoietic malignancies, whereas other solid neoplasms occurred less often than expected. Baird and Sadovnick 1, examining causes of death in DS patients before the age of 30, reported 8 leukemias and 1 Hodgkin's disease. Studies of mortality do not represent the true prevalence of cancers, as only certain malignancies are fatal. However, these publications favor the idea that lymphoma may be the most common solid malignancy in trisomy 21.

DS is associated with a progressive cell-mediated and humoral immune deficiency beginning in fetal life 21 and increasing during childhood and thereafter 15. The premature aging of the immune system 15 may well be an important risk factor for developing lymphomas, as both inherited and acquired aberrations of immune

1268 . D. Satge et al.

Fig. 1. Lymph node with extensive necrosis. HE x 20.

Fig. 2. Polymorphic centroblastic (large non cleaved) malignant lymphoma. HEx 630.

system are associated with this malignancylo. However, the fact that DS is also associated with an increased risk of other solid neoplasms such as testicular germ cell tumors 4, 11, indicates that other mechanisms may favor neoplastic transformation in this disease. Lorenzana and Schorin 10 reviewed the known possible mechanisms: 1) alteration of biochemical pathways involved in differentiation or function of different organs, 2) impair DNA repaired, 3) increased stem cell mutation rate, 4) increased transformation by oncogenic viruses and mutagens, 5) increased activity of on-

cogene proteins encoded on chromosome 21. Our patient had a t (14; 21) Robertsonian translocation. Balanced translocations, including Robertsonian translocations, have been found in significant excess in patients with solid tumors 19 • For example, there have been several reports of hematological disorders associated with a t (14; 21) transiocation 5 .It has been suggested that this might be due to the involvement of chromosome 14 in this rearrangement 5 • We suggest that this rearrangement may have favored the onset of the lymphoma in our patient. However, another me-

Down Syndrome and Lymphoma . 1269

chanism may be involved, as another patient with lymphoma and OS had a t (21q; 21q) Robertsonian translocation or isochromosome 21q without involvement of chromosome 14. Finally, all 7 patients in whom th~ sex is known were males. This suggests the possible eXIstence of a sex predisposition for malignancy in OS. The profoundly autistic state of our patient precluded normal pretherapeutic check-up and usual treatment procedures. His clinical course can therefore be considered to reflect the natural history of the disease. For other patients with OS and less important mental retardation therapeutic measures are more likely, however with frequently reported unusually severe side effects of chemotherapy8, 18. Acknowledgements We are grateful to Dr. J. c. Bouyat for kind collaboration and to B. Bezamat for secretarial assistance.

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Received May 5, 1995 . Accepted in revised form October 15, 1996

Key words: Down Syndrome - Centroblastic Lymphoma - Robertsonian Translocation Daniel Satge, Laboratoire d' Anatomie Pathologique, CH Tulle 19012, France, Tel.: (33) 555-29-79-13, Fax: (33) 555-29-79-31