Brandon Guthery, M.D., Kar-Ming Fung, M.D., Ph.D. Last update: May 31, 2006.

Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Clinical information:  The patient was a 75 year-old, right handed man who developed some progressive weakness over the last few month. There was also some right facial weakness. His weakness progressed to the point the he had multiple falling. The patient also complained of lost of balance, generalized weakness, and lost of coordination.. There was no complain of headache. There was also a history of colon cancer with surgery 6 years before the current presentation. He also had remote tonsillectomy and adenoidectomy.

On physical examination, the patient was alert to time, place, person and current events. The speech and compresension were fluent and intact. No cranial nerve abnormalities were found. Systemic workup did not reveal any other mass or space occupying lesion. On MRI, there were several intra-axial, diffusely and irregularly enhancing masses in the right cerebral hemisphere, right cerebellar peduncle, and the pons. A biopsy was performed.  Representative photomicrographs are show in the followings:

A. Squash DiffQuick	B. Squash DiffQuick	C. Squash	D. Frozen	E. Frozen	F.
G.	H.	I.	J.	K.	L. Reticuin
M. LCA	N. LCA	O. CD3	P. CD3	Q. CD20	R. CD20

Pathology of the case:

• Intraoperative consultation: Squash preparations were performed and stained with DiffQuick (Panel A and B) and hematoxylin-eosin (Panel C) respectively. The majority of the cells are composed of small lymphocytes but some large, atypical lymphocytes were also present. The large cells were more easily seen in DiffQuick stain. On Frozen section, the lesion appeared to be a densely packed small blue cell lesion most consistent with a lymphoid proliferative process (Panel D). On high-maghification, some large, atypical cells were present among the smaller lymphocytes (Panel E). A frozen section diagnosis of atypical lymphoid proliferation was made. It is often very fruitful to perform a DiffQuick stain if a diagnosis of atypical lympoid proliferation is suspected as illustrated in this case. The morphology appears much better then the hematoxylin-eosin stained squash preparation.
• Flow cytometry: Based on the frozen section diagnosis, a portion of tissue was submitted for flow cytometry. The flow cytometry results indicated that over 99% of the cells were T-cells.
• Permanent sections: The lesion was featured by infiltrating small, blue cells that involve both the parenchyma (Panel F) and leptomeningeal-subpial region (Panel G). In some areas, the lesion was composed of a mixture of small and large, atypical lymphocytes (Panel  H and I). In other areas, the proportion of large, atypical cells were substiantially increased (Panel J and K). A reticulin stain demonstrated dissection of the reticulin fiber which lead to a patter reminiscent of the cross section of an onion (Panel  L). Many but not all of the lymphocytes are positive for leukocyte common antigen (LCA) (Panel M and N). Most of the lymphocytes are positive for the T-cell marker (CD3) and, in particular, the large atypical cells are positive for CD3 (Panel O and P). This feature cannot be well appreciated on the screen but under the microscope. Very few B-cells are present as demonstrated by the B-cell marker (CD20) (Panel Q and R). CD10 and CD30 were negative in the atypical lymphocytes. The immunohistochemistry results concurred with the flow cytometry result.
• Molecular pathology: Monoclonal T-cell receptor gamma chain gene rearrangements were detected by polymerase chain reaction (PCR).

Comment: The initial clinical impression was metastases because of the history of colon cancer and multiple, irregular, enhancing lesions. The morphology and immunohistochemical profile were suggestive of a T-cell lymphoma and the diagnosis was confirmed by molecular pathology studies.

Discussion:     Introduction    Etiology    Clinical Manifestation    Neuroimaging    Pathology    Molecular Pathology

Introduction

    Primary central nervous system lymphoma (PCNSL) is a rare tumor. Before the advent of modern diagnostic techniques including immunohistochemistry and molecular pathology techniques, its nature was not exactly clear. In fact, they were first described by Percival Bailey as “perithelial sarcoma” because of its strong tendency to develop perivascular infiltration ¹. By definition, PCNSL must originate in the central nervous system but not resulted from secondary involvement by a lymphoma in other parts of the body.

    In immunocompetent individuals, PCL is an uncommon tumor that occurs in eldery age group. They account for approximately 5% of all primary brain tumors and 1-2% of non-Hodgkin’s lymphoma (NHL) ^{2 , 3,  4}.  The large majority of PCNSL are of B-cell origin; T-cell lymphomas are seen rarely and have a reported 3.6- 8.5% rate of incidence in recent large series studying PCNSL ^{5, 6}. In the largest series of PCNSL cases diagnosed in Western countries, T-cell origin has been reported in 8 (2%) of 370 cases ⁷.  The male to female ratio is 1.5-2:1. Primary Hodgkin’s lymphoma is almost unknown in the central nervous system. Studies have shown that the prognosis for patients with T-Cell PCNSL is similar to that for B-cell PCNSL, with cytologic type (small vs. large) having no effect on survival ¹⁰.

    In immunocompromised individuals, it can affect any age group and the time of onset is related to both the time of onset and type of immunosuppression or immunodeficiency. In general, there is a peak in patients under 10 years of age which are probably resulted from congenital immunodeficiency. Another peak occurs at around the 4^th decade which is probably related to HIV infection, immunosuppression due to solid organ transplantation, and other causes of immunosuppression. Theoverall survival for treated patients is much better for patients without AIDS than for those with AIDS. [See related case1] [See related case 2] [See related case 3]

Etiology

    Multiple theories exist on the origin of PCNSL. One proposed theory is based upon the immunologically privileged environment in the brain. This theory suggests that the malignancy develops outside the CNS originally and the immune system eliminates any peripheral involvement. An argument against the immunoprivileged theory is that patients with PCNSL do not develop lymphoma in other immunologically privileged sites, such as the testes.

    Another theory suggests a central inflammatory process results in the trafficking of lymphocytes into the brain, where they undergo neoplastic transformation. The inflammatory theory has two arguments against it. First, T cells, not B cells, normally traffic through the CNS, yet the vast majority of PCNSLs are of B-cell lineage. Second, there is no association between cerebral inflammatory diseases such as multiple sclerosis, encephalitis, or bacterial infections, and the development of PCNSL.

    In immunocompromised individuals, Epstein-Barr viruse is often the etiologic agent. There is a predeliction for the production of B-cell lymphoproliferative diseases in patients receiving cyclosporine. In patients with solid organ transplantation, many of the lymphoma evolves as a postransplantation lymphoproliferative disorder (PTLD) which is a polyclonal or oligoclonal proliferation. The resulting monoclonal proliferation is typically in the form of a high-grade B-cell lymphoma.

Clinical Manifestation

    Neurological symptoms present at diagnosis depend on the location of the lesion. Similar to many other space occupying lesions, the symptoms are quite non-specific. Focal motor defects are the most common symptom. Changes in personality, cognitive difficulties, and headache are common. Seizures can be seen as well. The average time from onset of symptoms to diagnosis is weeks to months, but it may be longer if personality change is the only presenting symptom ⁸.

Neuroimaging

    The MRI findings are quite different in PCNSL occurring with and without association with AIDS, PCNSL that occurs in AIDS patients are often multifocal and centrally necrotic and appear as ring-enhancing lesions. The later features often lead to the clinical impression of a glioblastoma or metastases.

    In PCNSL that are not occurring in AIDS setting, they are also common to be multiple. In particular, they tend to present as multiple, symmetrical, bilateral and subependymal foci. In contrast to those occurring in AIDS, these tumor are typically non-necrotic and without ring enhancement. In fact, enhancement is rather homogeneous.

Pathology

    Primary CNS lymphomas (PCNSL) can be firm, friable, granular, centrally necrotic, focally hemorrhagic, grey-tan, yellow, or virtually indistinguishable from the adjacent neuropil. Some tumors are well-delineated, like a metastasis; while some present as diffusely infiltrating forms without evidence of mass lesions. Multiple lesions are seen in about one-third of the patients. Typically, they are deep-seated in the cerebral hemispheres and are adjacent to the ventricules. Less commonly PCNSL are superficially located and one study showed an increased incidence of this with T-cell PCNSL ⁹. A small proportion of them are limited only to the dura.

    Microscopically, the morphology is similar to the corresponding type of lymphoma that occurs in other parts of the body. The neoplastic cells demonstrate a classic perivascular infiltration that dissects the perivascular reticulin network. Geographic necrosis may be seen when tumors become confluent, with perivascular islands of viable tumor cells surrounded by large regions of coagulative necrosis. As most of the PCNSL are of diffuse large B-cell type, the neoplastic cells are typically highly pleomorphic and large. Low-grade lymphomas are relatively uncommon.

Their immunohistochemical profiles are similar to lymphomas that occur outside the central nervous system. Intraoperative recognition of an atypical lymphoproiferative lesion is important as fresh tissue can be sent for flow cytometry which is often an important adjunct for correct diagnosis.

Molecular Diagnosis and Cytogenetics

    While B-cell lymphomas can often be diagnosed by immunohistochemisty and flow cytometry particularly when light chain restriction is recognized, the confirmation of a T-cell lymphoma is heavily relied on molecular pathology. particular, rearrangement of T-cell receptors in a clonal pattern is a strong evidence for diagnosis. This is particularly true for the distinction of T-cell lymphoma from reactive inflammation which contains a substantial amount of T-cells. Molecular pathology is also useful in the differential diagnosis of T-cell lymphoma from T-cell rich B-cell lymphoma.

Reference

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