Departments of 1 Pathology, 2 Hematology, 3 Radiochemotherapy, 4 Neuroradiology and 5 Neurosurgery, S Raffaele H Scientific Institute, Milan; 6 Department of Pathology, Ospedale S Maria Della Misericordia, Udine, Italy
Received 13 November 2001; revised 17 April 2002; accepted 8 May 2002
Abstract
Background:
Primary central nervous system lymphomas (PCNSLs) are rare tumors, mostly represented by diffuse large B cells. PCNSLs with a T phenotype are less frequently reported; even rarer are anaplastic large cell lymphomas (ALCLs). PCNSL ALCLs are commonly represented, like their systemic counterpart, by a variably prevalent amount of large pleomorphic tumor cells (hallmark cells), and this feature enhances their recognition.
Patient and methods
We report the first case of primary brain CD30+ ALK-1+ ALCL with a T-cell phenotype, showing the combination of both the lymphohistiocytic and the small cell variants of the disease. A few elements consistent with hallmark cells were recognizable. However, these cells were never prominent, increasing diagnostic difficulties. Immunohistochemistry results were critical for the correct interpretation. Our findings also differ from the majority of PCNSL ALCLs for the absence of tumor necrosis and the lack of prominent mitotic activity. The neuroimaging picture was not specific. A comparison with literature data concerning the clinical/instrumental features shows a very frequent meningeal involvement in PCNSL ALCLs, in contrast to the majority of PCNSLs.
Conclusion:
The occurrence of such a rare form of ALCL may widen the spectrum of differential diagnoses in PCNSL and their recognition may allow a rapid diagnosis, thus encouraging adequate treatment, which should take into account the high rate of meningeal involvement observed in these cases.
Key words: ALK, anaplastic, brain, central nervous system, hallmark cell, lymphoma
Introduction
Primary central nervous system lymphoma (PCNSL) is a rare malignancy (0.51.5% of all brain neoplasms) [1], although its incidence is increasing, also in immunocompetent individuals [2]. The vast majority of PCNSLs are represented by large cell forms and display a B-cell phenotype. T-cell PCNSL is uncommon [3]; even rarer are anaplastic large cell lymphomas (ALCLs) [4].
In the present report, a case of PCNSL CD30+ ALK-1+ ALCL with a T-cell phenotype in a young immunocompetent adult is described. The morphological features of the lesion, consistent with an admixture of not-common variants of the disease, as well as clinical, instrumental and therapeutic management characteristics, are analyzed and compared with literature data; in particular, the critical diagnostic role of immunohistochemistry is acknowledged. Finally, the impact of ALCL diagnosis on therapeutic management of PCNSL is discussed.
Case report
A 29-year-old man was admitted to hospital because of fever, headache and generalized seizures, arising a few days earlier. After a crisis of generalized seizures, a reduction of spontaneous speech was observed. The results of a general physical examination were normal. On neurological evaluation no defects in motor sensitivity were observed. A lumbar puncture showed clear colorless fluid, 5 lymphocytes/mm3 and a protein content of 53 mg/dl (normal value 1560 mg/dl). Neither malignant cells nor microorganisms were seen, and cultures were negative. An unenhanced computed tomography (CT) brain scan and magnetic resonance imaging (MRI) failed to show any abnormality. On a clinical basis, acute meningitis was diagnosed and the patient was discharged with antibiotics, obtaining remission of fever and headache.
Two weeks later the patient was re-admitted with further generalized seizures; after the crisis a motor/sensitive defect in the right hemibody was persistent for a few days. A brain CT scan showed the presence of a hypodense edematous corticalsubcortical fronto-temporal lesion. Enhanced MRI of the brain better defined the lesion, showing the presence of a cortical frontal enhancing nodule surrounded by edema; the lesion appeared hypointense on T2-weighted images and after injection of gadolinium it enhanced strongly and homogeneously; some pial and subarachnoid enhancement was also present close to the lesion. In consideration of the clinical and imaging evolution, the lesion was interpreted as a probable infective localization, and multiple combinations of antibiotics were therefore administered. A further brain MRI performed 2 weeks later showed progression of the lesion resulting in multiple, confluent enhancing nodules mostly cortical in location and dislocated around the left sylvian scissure (Figure 1A and B); pia and subarachnoid enhancement persisted although less evidently, whereas edema was increased together with the mass effect. With the suspicion of the presence of an underlying progressive lesion, an open brain biopsy was performed, which concluded that there was a picture consistent with reparative changes of a former abscess. Systemic steroid treatment was then added to ceftriaxone, producing cessation of fever and partial seizures.
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A second open brain biopsy was therefore performed. At surgery, the pathological tissue showed hypervascularization and firm consistency. Cultural analysis made on a portion of the specimen showed no microorganisms. Histological examination revealed a population composed of medium-to-large lymphoid-looking cells; the latter showed slightly kidney-shaped nuclei devoid of prominent nucleoli and relatively abundant cytoplasm. A few of these cells were consistent with hallmark cells, but they were never prominent and homogeneously smaller than those encountered in the common variant (Figure 2A). The neoplastic elements were immunoreactive for leukocyte common antigen, CD30 (Figure 2B), ALK-1 (Figure 2B, insert), epithelial membrane antigen, monoclonal CD3 and CD45RO but not for CD20, CD79a, S-100 protein, glial fibrillary acidic protein, myeloperoxidase, CD34 or CD68 (KP-1). Necrosis or prominent mitotic activity (i.e. more than 10 mitoses/mm2) were absent; moreover, some apoptotic figures were evident. In some areas, tumor cells were obscured by the preponderance of macrophages, and revealed a heavy inflammatory infiltrate, mainly represented by granulocytes and small lymphocytes. This aspect prompted us to re-evaluate critically the initial series of biopsies; the latter disclosed one small area with the same characteristics. A diagnosis of CD30+ ALK-1+ systemic ALCL was made [5]. Cerebrospinal fluid (CSF) cytological examination was repeatedly negative, as well as HIV serology. CSF protein level was increased (604 mg/dl).
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Discussion
Our case of PCNSL ALCL shows peculiar morphological features in the brain. To the best of our knowledge, this is the first case of combination of not-common variants of ALCL in the CNS. The neoplastic elements were predominantly medium-to-large sized, while only occasional cells consistent with hallmark cells were seen (Figure 2A). In addition, lymphomatous cells were admixed to a significant amount of CD68+ macrophages, masking the diagnostic cells in some microscopic fields, and other inflammatory cells, like small lymphocytes, plasma cells and granulocytes. The above mentioned features are consistent with a mixture of both the small cell variant and the lymphohistiocytic variant of ALCL [5]. The potential confusion in the above-described picture is confirmed also by the difficulty of its recognition in the first series of biopsies evaluated, and the presence of the reactive cellular milieu may also raise differential diagnostic problems with non-neoplastic process, mainly represented by abscesses. Within such a background, CD30 immunostaining (Figure 2B) permitted a better estimation of the neoplastic infiltrate, while ALK-1 staining (Figure 2B, insert) appeared critical in reaching the correct diagnosis, since virtually all the tumor cells were reactive for this marker. High mitotic rate [1, 610], as well as necrosis [1, 711] is usually described, in contrast with the present and previous experience [12].
ALCL was defined as a new category in 1985 [13] and as a clinico-pathological entity by the Revised EuropeanAmerican Classification of Lymphoid Neoplasms (REAL) classification scheme [14], where only cases with T or null (i.e. non-B, non-T) phenotype were considered. ALCL with a B-cell phenotype was therefore included in the group of diffuse large B-cell lymphomas. The most common extranodal sites involved include skin (21%), bone (17%), soft tissues (17%), lung (11%) and liver (8%) [15]. ALCLs rarely arise in the CNS, particularly in the brain. When using REAL and WHO classification criteria, only eight cases in immunocompetent patients have been reported so far in the English language literature [1, 612]. In the seven cases with available detailed histological description [1, 712], the classic variant was almost constantly reported with the exception of a case of lymphohistiocytic variant [11] (Table 1). We describe for the first time the coexistence of two rare variants, the lymphohistiocytic and the small cell one; this occurrence is per se quite rare, since it has been stated that more than one variant within an individual patient can be seen in approximately 10% of ALCLs [16]. Including our case, ALK-1 immunoreactivity has been reported in two instances [8]. In our experience, this marker was helpful in the differential diagnosis of T-cell PCNSL, actually being critical for the definition of that particular type of lymphoma defined as ALKoma [16]. A comparison with the previously published results is difficult, since ALK-1 immunoreactivity was rarely tested [8, 11]. Our findings really question if some of the previously reported primary T-cell PCNSLs may actually be forms of CD30+ ALK-1+ ALCLs.
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The rapid recognition of PCNSL ALCL, even without the morphological features of the classic variant, may therefore be helpful in permitting a more tailored therapeutic approach.
Footnotes
+ Correspondence to: Dr M. Ponzoni, Department of Pathology, S Raffaele H Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. Tel: +39-02-26432544; Fax: +39-02-26432409; E-mail: ponzoni.maurilio{at}hsr.it
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