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|LETTER TO EDITOR
|Year : 2015 | Volume
| Issue : 2 | Page : 276-279
CD45-negative primary diffuse large B-cell lymphoma of the cerebellum
Bhawna Jha, Ishani Mohapatra, Smeeta Gajendra, Ritesh Sachdev
Department of Pathology and Lab Medicine, Medanta The Medicity, Sector 38, Gurgaon, Haryana, India
|Date of Web Publication||5-May-2015|
Department of Pathology and Lab Medicine, Medanta The Medicity, Sector 38, Gurgaon, Haryana
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Jha B, Mohapatra I, Gajendra S, Sachdev R. CD45-negative primary diffuse large B-cell lymphoma of the cerebellum. Neurol India 2015;63:276-9
A primary central nervous system (CNS) lymphoma is a rare malignancy representing 4% of all intracranial neoplasms.  Monoclonal antibodies directed against the leukocyte common antigen (CD45) is a first-line marker for differentiating between lymphomas (CD45+) and poorly differentiated non-hemopoietic tumors (CD45-). The loss of CD45 expression has been described in rare cases of large B-cell lymphoma (LBCL) subtypes with an extranodal involvement. ,, We report a case of a primary diffuse large B-cell lymphoma (DLBCL) of the cerebellum in an immunocompetent female, that morphologically and radiologically mimicked an undifferentiated metastatic carcinoma. In a known case of carcinoma, CD45 negativity may pose a diagnostic challenge when one is attempting to differentiate primary lymphoma from metastatic non-hemopoietic tumors. To the best of our knowledge, this is the first report of a CD45-negative primary DLBCL of the cerebellum in the medical literature.
A 63-year-old-female patient presented in the neurology outpatient department with a history of seizures. She had a past history of undergoing a modified radical mastectomy for carcinoma breast 8 years ago. She also had a history of pulmonary tuberculosis, for which she had received anti-tuberculous drugs for 18 months about 3 years ago. Her physical examination was unremarkable. The hemogram, X-ray Chest and electrocardiograph tests were normal. Her magnetic resonance imaging (MRI) of the brain revealed a large, well-defined lobulated lesion in the left cerebellar hemisphere showing a moderate enhancement with central necrotic areas and associated mass effect on the dorsolateral aspects of the pons and medulla [Figure 1]. The possibility of a metastatic/tubercular etiology was suggested. Shortly after the MRI, she underwent a left retromastoid craniotomy and tumor excision to relieve the mass effect. An intra-operative frozen section revealed a poorly differentiated high-grade tumor with necrosis. Excisional biopsy showed the cerebellar tissue infiltrated by atypical large cells having a nesting arrangement, and a desmoplastic stroma separating the tumor cell nests [Figure 2]a. The cells had a high nucleo- cytoplasmic ratio, hyperchromatic nuclei with brisk mitosis and areas of necrosis. In view of the morphological and MRI findings in a previously diagnosed case of breast carcinoma, a likely diagnosis of a high-grade metastatic undifferentiated carcinoma was made and immunohistochemistry was ordered. The first-line immunohistochemistry tests revealed the tumor cells to be negative for Leukocyte Common Antigen (Dako, Produktionsvej 42 Glostrup Denmark; 2B11 + PD7/26) [Figure 2]b, Cytokeratin (Biogenix, San Ramon CA, USA; AE1 + AE3), Synaptophysin (Dako; SY38) and Glial fibrillary acidic protein (Dako; IS524). Further immunohistochemistry subsequently revealed these cells to be positive for CD20 (Dako; L26 [Figure 2]c, CD79a (Dako; JCB 117), CD10 (Dako; 56C6) and MUM-1 (Dako; Mum1p) and negative for TdT (Dako; IS001), Anaplastic lymphoma kinase (Dako; ALK1), CD138 (Dako; MI15), CD99 (Dako; 1.20E + 008), Bcl6 (Dako; PG-B6p), CD3 (Dako; IS503) and Epstein Barr virus (Dako; CS1-4). The Ki-67 labeling index was approximately 80-85% [Figure 2]d. A diagnosis of a high-grade B-cell non-Hodgkin's lymphoma of the cerebellum was made. She was serologically negative for human immunodeficiency virus (HIV). The whole-body positron emission tomography (PET) did not reveal any other FDG avid lesions. After a left retromastoid craniotomy and tumor excision, the patient was started on a high-dose (intrathecal methotrexate with rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. After two cycles of chemotherapy, the patient was lost to follow-up.
|Figure 1: Magnetic resonance imaging revealed an oval, enhancing mass lesion in the left cerebellar hemisphere compressing the brain stem and the fourth ventricle|
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|Figure 2: (a) Excisional biopsy showed the cerebellar tissue that was infiltrated by a poorly differentiated malignant tumor having a nesting arrangement separated by desmoplastic stroma. Tumor cells had a high nuclear-cyto plasmic ratio, hyperchromatic nuclei and brisk mitosis (hematoxylin and eosin, ×200, inset ×1000). Immunohistochemistry showing malignant cells to be CD45 negative (b, ×400) and CD20 positive (c, ×400), with an 80-85% Ki67 index (d, ×400)|
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Monoclonal antibodies (mAbs) directed against the leukocyte common antigen (CD45) have been proposed as a useful tool for differentiating between lymphomas (CD45+) and poorly differentiated non-hemopoietic tumors (CD45-). The CD45 antigen is expressed on all nucleated hematopoietic cells (with the exception of erythroid progenitors and a small fraction of normal bone marrow plasma cells); hence, the B-lymphocytes and their pathological counterparts are expected to positively stain with an anti-CD45 mAbs. The loss of CD45 expression in a B-non-Hodgkin lymphoma is a very unusual phenotype, being more frequently observed in an immature B-cell neoplasia. It is undetectable in most lymphoblastic lymphomas and is variably expressed in plasma cell neoplasms and in anaplastic large T-cell lymphomas.  CD45 negativity is rarely documented in large B cell lymphomas. The few CD45-negative LBCL cases that have been reported in the literature had an extranodal presentation and were classified as a anaplastic lymphoma kinase (ALK)-positive LBCL or as a plasmablastic lymphoma. ,,, Several investigators have reported that CD45 expression was frequently lacking in patients with a plasmablastic lymphoma. A case of CD45-negative diffuse large B-cell lymphoma is described in the thyroid gland, but it had a plasmablastic/plasmacytoid differentiation.  A rare case of CD45- large B cell lymphoma with no extranodal lesions is also described in a patient with lymph node and blood marrow involvement by flow cytometry immunophenotyping.  There are several posulates explaining the loss of CD45; the actual reason is, however, not well clarified. It has been known that expression of CD45 antigen by hematopoietic cells is dependent on both cell differentiation and proliferation. In a normal B-cell lineage, CD45 is expressed in a low intensity by the progenitor cells, whereas it is expressed in progressively higher amounts by maturing B lymphocytes, and then finally lost during the terminal differentiation to plasma cells.  Loss of CD45 expression on lymphoma cells usually suggests that neoplastic transformation occurred during the differential pathway to plasma cells just before its CD20 expression. In our case, as there was no plasma cell differentiation, there is no plausible explanation for CD45 negativity. CD45 negativity could possibly represent the high proliferative activity of the lymphoma cells in our case. This suggestion seems to be supported by the high Ki-67 labeling index in our patient. The CD45 expression observed in the residual lymphocytes present within the tissue section, which were smaller in size than the lymphoma cells, served as an internal control for the staining procedure and antibody validation. These residual small lymphocytes were also positive for CD3. Also, the anti-CD45 mAbs used in the present case are a mixture of two monoclonal antibodies, clones 2B11 and PD7/26, which are directed against different epitopes and react with all the known isotypes of the CD45 family; therefore, loss of CD45 expression was not epitope specific.  The awareness of this potential diagnostic pitfall is of great importance because of the fact that a primary CNS lymphoma may rarely be CD45 negative and thus may easily be misdiagnosed as a metastatic carcinoma, which is the most common malignant neoplasm encountered in the CNS. These cases may be extremely challenging as cytokeratin has sometimes been reported to be expressed on CD45-negative lymphoma cells.  On the other hand, a cautionary note that should be borne in mind is that, exceptionally, an undifferentiated carcinoma or neuroendocrine carcinoma may be focally, strongly positive for CD45 while being positive for cytokeratin at the same time.  This case emphasizes that, in a known case of carcinoma, a negative CD45 does not absolutely preclude the diagnosis of a lymphoma in tumors having a large cell undifferentiated tumor morphology. It is recommended that a primary lymphoma should be borne in mind and CD20 determination must be kept in the initial workup of an undifferentiated tumor in the CNS.
In conclusion, we report the first case of a CD45-negative primary DLBCL of the CNS in an immunocompetent patient that involved a rare site, the cerebellum. The tumor, morphologically and radiologically, mimicked an undifferentiated metastatic carcinoma.
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[Figure 1], [Figure 2]