April 2014

A 62-year-old male with a past medical history of hypertension

Majed M. Pharaon, M.D., Kym Gyure, M.D., Matthew Smolkin, M.D.

Overview

A 62-year-old male with a past medical history of hypertension, atrial fibrillation, alcohol and nictotine abuse and no past surgical history presented to the emergency department with a syncopal episode without any prodromal symptoms. There was no reported bowel incontinence or seizure-like movements. Additionally, the patient reported a 2 month history of urinary incontinence followed by back pain and left leg pain. Physical examination, complete blood count, and basic metabolic profile were within normal limits. A CT scan of the brain without intravenous contrast showed multiple lesions in the right frontal lobe, left frontal lobe, and lateral ventricle and a MRI of the brain showed multiple enhancing lesions. Whole body imaging showed no lymphadenopathy. A biopsy from the right frontal lesion was performed (see figures 1 - 8).

Gross and Microscopic Description

Gross

The specimen was labeled as right frontal tumor and consisted of four tan tissue fragments ranging from 0.3 cm to 0.7 cm in greatest dimension.

Microscopic

The biopsy shows infiltration of the brain tissue by atypical lymphoid cells. These cells are intermediate to large with ovoid to irregular nuclei, occasional nucleoli and minimal to moderate cytoplasm. Occasional mitotic figures are seen. The brain tissue around the tumor cells demonstrates features of gliosis. Immunohistochemical stains were performed and are shown in the figures below.

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Figure 1: (100X) H&E section of the right frontal tumor.
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Figure 2: (400X): H&E section of the right frontal tumor; arrow points to a mitotic figure.
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Figure 3: (A) (200X) CD3 Immunohistochemistry (IHC). (B) (100X) CD2 IHC.
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Figure 4: (A) (200X) CD5 IHC. (B) (200X) CD7 IHC.
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Figure 5: (200X) CD20 IHC.
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Figure 6: (A) (200X) CD30 IHC. (B) (200X) ALK-1 IHC.
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Figure 7: (200X) Ebstein-Barr virus (EBV) In Situ Hybridization (ISH).
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Figure 8: (100X) Ki-67 IHC; approximately 70% of the atypical cells are labeled with Ki-67

Diagnosis

Given the clinical history, gross and microscopic findings and immunohistochemical staining profile, which of the following would be the most likely diagnosis ?

Answer

Please select an answer above.

Discussion

Primary CNS lymphomas (PCNSL) are defined as extranodal lymphomas arising within the CNS in the absence of lymphoma outside the CNS at the time of diagnosis. PCNSL in immunocompetent individuals are rare and account for approximately 5% of all brain tumors and < 1% of Non-Hodgkin lymphomas. Males are affected more than females with a ratio of 3:2 [1,2]. Immunodeficiency disorders such as Wiskott-Aldrich and AIDS predispose to the development of PCNSL. The Epstein-Barr virus (EBV) genome is found in more than 95% of immunocompromised patients and only in 0-20% of immunocompetent patients [2]. Most patients present with focal neurological deficits and around 5-20% present with seizures. MRI is the most sensitive radiologic modality for the detection of CNS lymphomas. It characteristically shows single or multiple enhancing lesions which can be seen in other brain lesions such as glioblastomas, brain abscesses, and metastatic carcinomas.  

More than 95% of PCNSL are diffuse large B-cell lymphomas. CNS T-cell lymphomas constitute 2-5% of all primary CNS lymphomas. They are more common in Korea and Japan constituting 17% and 8-14% of all PCNSL, respectively [4]. Histologically, the tumor displays an atypical lymphocytic infiltration. These cells are intermediate to large with ovoid to irregular nuclei, occasional prominent nucleoli, and minimal to moderate cytoplasm (figure 1). Mitotic figures are usually present (figure 2). The brain parenchyma surrounding the tumor has features of gliosis. 

Immunophenotype

Typically, the tumor cells express the pan T-cell antigens CD2, CD3, CD5, and CD7; however aberrant loss of one of these antigens is common [3]. B-cell markers are typically negative. The atypical cells in this case are strongly positive for CD2 and CD3 (figure 3), with an aberrant loss of CD5 and partial loss of CD7 (figure 4). There is positivity for CD20 in few scattered B-cells (figure 5). Other immunohistochemistry stains were utilized in this case for further classification and prognostic value (see below). 

Differential diagnosis

Since primary CNS T-cell lymphoma is extremely rare, a tumor with the previously mentioned immnophenotype would be classified as a peripheral T-cell lymphoma, not otherwise specified. However, the absence of lymphadenopathy supports the diagnosis of a primary CNS T-cell lymphoma. Anaplastic large cell lymphoma is an important differential diagnosis but the absence of staining for the characteristic CD30 and ALK-1 (figure 6) excludes this diagnosis. A poorly differentiated metastatic carcinoma or a malignant melanoma should be also ruled out.   

Treatment and prognosis

PCNSL are very aggressive and have poor prognosis. Current available therapeutic modalities are whole brain irradiation, systemic chemotherapy, and intraventricular chemotherapy. Methotrexate is the most efficient cytotoxic drug added to the chemotherapy regimen and is associated with better survival [5]. Surgical resection of the tumor does not have a survival benefit [6]. Additionally, a high index of Ki-67 staining is associated with a worse prognosis.

References

  1. World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th Edition. International Agency for Research on Cancer. Lyon, 2008.
  2. World Health Organization Classification of Tumors of the Central Nervous System. 4th Edition. International Agency for Research on Cancer. Lyon, 2007.
  3. Hematopathology.  2nd Edition. Eric D. His, M.D.
  4. Choi JS, Nam DH, Ko YH, Seo JW, Choi YL, Ree HJ (2003). Primary Central Nervous System Lymphoma in Korea: Comparison of B- and T-cell Lymphomas. Am J Surg Pathol 27: 919-928.
  5. Shenkier et al (2005). Primary CNS Lymphoma of T-Cell Origin: A Descriptive Analysis From the International Primary CNS Lymphoma Collaborative Group. J Clin Oncol 23:2233-2239.
  6. M. Bellinzonaa, F. Rosera, b, H. Ostertagc, R.M. Gaaba, M. Sainid (2005). Surgical removal of primary central nervous system lymphomas (PCNSL) presenting as space occupying lesions: a series of 33 cases. European Journal of Surgical Oncology 31: 100-105.