Journal of Neuro-Oncology 47: 141–144, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Clinical Study
Primary central nervous system lymphoma and subcutaneous metastases Bassim Al Bahrani1 , Chris Henderson2 and Geoff Delaney1 Radiation Oncology Department, Cancer Therapy Centre, Liverpool Hospital, 2 Anatomical Pathology, South Western Area Pathology Services, Liverpool Hospital, Liverpool, Australia
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Key words: subcutaneous, metastasis, lymphoma, CNS lymphoma Summary Primary central nervous system lymphoma (PCNSL) is a rare disease with a poor prognosis. It usually remains confined to central nervous system (CNS). Reports of metastases outside of the CNS are rare. We report a patient with well-documented PCNSL who responded to treatment, but subsequently developed a histologically confirmed subcutaneous metastasis to the left leg without local failure.
Case report L.B. is a 64-year-old male who presented in March 1997 with a two months history of left-sided weakness, intermittent headache, confusion, and speech disturbance. Neurological examination revealed he was confused and there was mild left sided weakness with grade 4/5 power in left upper and lower limbs, with normal sensation, coordination and gait. Fundoscopic examination was normal. Other physical examination was normal. In particular there was no lymphadenopathy or hepatosplenomegaly and no skin lesions were noted. Blood examination showed normal electrolytes, renal and liver function tests. Complete blood count, uric acid, and lactate dehydrogenase were normal. A contrast enhancing computerized tomography (CT) scan of the brain revealed a right basal ganglia lesion with associated mass effect. Serology for human immunodeficiency virus (HIV) was negative. Bone marrow aspirate and biopsy, gallium and thallium studies were normal. Stereotactic brain biopsy was performed. Histology showed a dense, mainly perivascular infiltrate of large atypical lymphoid cells within the cerebral tissue (Figure 1a,b). The cells stained strongly with a marker for B-lymphocytes (CD20), the features were reported as B cell lymphoma. He was treated using the Trans Tasman Radiation Oncology Group (TROG) phase II protocol for CNS
lymphoma (TROG 92.01). This consists of high dose intravenous methotrexate 1 g/m2 on days 1 and 8 followed by cranial irradiation. Radiotherapy consisted of 39.6 Gy to the whole brain followed by a 10 Gy boost with left and right lateral 6 MV fields, and was commenced on day 15. There was a good response to treatment with significant improvement in his neurological symptoms. Radiologically he had a complete response. He remained well and asymptomatic until he was admitted to hospital in September 1997 with the development of a painless subcutaneous nodule in the calf of the left leg (Figure 2). Skin biopsy showed a heavy diffuse infiltrate of large atypical non-cleaved (centroblastic) lymphoid cells in the dermis and subcutis (Figure 3a,b). Immunoperoxidase stains of leukocyte common antigen (LCA) and CD20 were strongly positive, consistent with a diagnosis of diffuse large B-cell non-Hodgkin’s lymphoma (NHL). The morphology of thc lymphoid cells was similar to that seen in the CNS biopsy. Staging investigation included thallium scan which was normal and gallium scan which showed abnormal increased focal uptake in the left leg just below the knee. CT scan of the chest revealed no evidence of any mediastinal or hilar masses, and magnetic resonance imaging (MRI) disclosed no evidence of recurrent primary central nervous system lymphoma (PCNSL).
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Figure 1a. Infiltration of cerebral tissue by large lymphoma cells (H & E, ×200).
Figure 1b. Strong immunoperoxidase staining (dark rimmed cells) of lymphoma cells with the L26 marker for CD2O (×400).
The subcutaneous nodule was treated with 12 MeV electron beam radiotherapy to a total dose of 39 Gy in 13 fractions. He did not receive any systemic treatment, as the patient was not considered fit for chemotherapy. He remains in complete remission from his PCNSL, and his left leg subcutaneous metastasis, with the last follow-up in October 1999. Discussion PCNSL tends to be an aggressive NHL because of the location and its usual intermediate to high grade morphology. Despite a rise in incidence they continue to remain uncommon tumors [1]. During the course of the disease they remain confined to the CNS in more than 90% of cases, and represent 4–6% of all primary brain tumors and 1–2% of all extranodal NHL [2], although higher percentage are occasionally reported.
Figure 2. Subcutaneous nodules in the shin of left leg.
Using the working formulation classification, the intermediate and high grade lymphomas account for 60–90% of most case series. Typically, the histology of these is of diffuse large cell, diffuse mixed cell type,
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Figure 3b. Strong immunoperoxidase staining (dark rimmed cells) of lymphoma cells with the L26 marker for CD2O (×400).
Figure 3a. Heavy dermal infiltrate of large lymphoma cells (H & E, ×200).
large cell immunoblastic or small cleaved cell types. Low grade lymphomas represent a minority of cases [3–5]. The highest incidence has been reported in patients with HIV infection. PCNSL is now the most common non-infectious space-occupying lesion in patients with acquired immunodeficiency syndrome (AIDS), however, there has been a dramatic rise in the incidence among apparently immunocompetent individuals [6]. PCNSL affects all ages, with a peak incidence in the sixth and seventh decade in immunocompetent patients and younger in immunosuppressed patients [6]. Both groups do poorly without therapy (1–3 months mean survival); the overall survival for treated patients is better for patients without AIDS (18.9 months) than for those with AIDS (2.6 month) [7]. Standard therapy has been whole brain radiotherapy, or cranio-spinal irradiation, combined with corticosteroids. The results of such treatment have been disappointing. The addition of
chemotherapy to radiotherapy has improved the prognosis. Although no large prospective trials have compared chemotherapy plus radiotherapy to radiotherapy alone, accumulating data from multiple phase II studies. and retrospective analysis clearly document the superior outcomes with combined modality therapy, showing a median survival up to 42 months, with a five-year survival of 22.3%, and a prolonged time to recurrence compared to patients receiving radiotherapy alone [2,6–11]. As patients with intensively treated PCNSL are living longer we may be changing the natural history of this disease and extending survival [7,12]. This may also change the pattern of recurrence such as the case illustrated here, even though the time interval to relapse may remain the same. Relapse occurs in most cases, and it is usually confined to the CNS (either to the original brain site, distant brain sites, leptomeninges or eye) accounting for 90–93% of relapse cases; 7–10% of cases will have systemic relapse. The most common sites of systemic relapses reported include kidney [5,13–15], lymph nodes [3,7,9,14,16,17], testicles [5,13,14], bowel, colon, and gastrointestinal tract [4,5,14,15]. Other more rarely reported sites include lung [13,15], adrenals [14], retroperitoneum [15], heart [4], mediastinum [18], breast [15], nasal cavity [8], skull [3], bone [15], and bone marrow [4]. Other reports have only reported distant sites of involvement as “outside CNS”, without being more specific about the anatomical location [11,16,19]. Other rare sites reported include nerve, liver, gall bladder, spleen, stomach, duodenum, and thyroid [3]. In our case, no cytogentics was performed and therefore we cannot be certain whether the intracranial
144 and subcutaneous lymphoma are two different tumors, or they are metachronous manifestations of the same disease. However the third possibility that the subcutaneous nodule was missed clinically at the time of PCNSL diagnosis is unlikely because primary subcutaneous lymphoma is a rare disease, the nodule was rapidly growing and it should have been noticed by the patient if it had been missed by us, and finally systemic relapse from PCNSL at 3–6 months has been reported by others [3,13]. We therefore postulate that the most likely event is that this represents a metastasis of PCNSL. We are not aware of any reported cases of PCNSL with subcutaneous metastases.
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Conclusion There is a rising incidence of PCNSL both in immunocompromised and immunocompetent patients but overall it remains an uncommon disease. With the use of combined modality therapy, and resulting increased survival the natural history of PCSNL appears to be changing. This seems to be associated with the probability that with better local control, the chances of systemic failure appear to be more likely with an associated change in the pattern of distant metastasis. We report a patient with PCNSL who developed subcutaneous metastases without local failure.
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Address for offprints/Correspondence: Dr. Geoff Delaney, Radiation Oncology Department, Cancer Therapy Centre, Liverpool Hospital, Locked Bag 7103, Liverpool BC NSW 1871, Australia; Fax: 02 9828 5299; E-mail:
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