1.Overview
Central nervous system lymphoma can be divided into two categories: primary and secondary. Secondary refers to non-Hodgkin’s lymphomas (NHLs) involving the central nervous system, which can manifest as lymphocytic molluscum contagiosum and epidural spinal cord compression signs. Primary central nervous system lymphoma (PCNSL) refers to lymphomas that are confined to the cranial-spinal cord midline axis and do not invade other systems throughout the body. PCNSL accounts for about 3% of intracranial tumors and less than 1%-4% of all non-Hodgkin’s lymphomas (NHLs).
The name PCNSL has undergone a series of evolutions, and in 1929 Bailey used the term “perineural cell sarcoma” when describing two cases of cranial tumors characterized by tumor cells originating from the reticuloendothelium and distributed around blood vessels. From the perspective of tissue or cell origin, the tumors were named as reticulocytic sarcoma, microglial cell tumor, peripheral vascular sarcoma and so on. It was not until the 1970s that the disease was found to be histologically identical to systemic lymphoma. By analyzing immunoglobulins on the surface of tumor cells, it was shown to be a B-lymphocytic NHLs, of which 1-3% can have a T-lymphocyte phenotype.
Systemic metastases are the most common cause of invasion of the central nervous system (CNS) by NHLs, but metastatic NHLs are more easily distinguished from PCNSL. Metastatic lymphomas metastasize to the CNS late in the disease via hematogenous metastasis, usually involving the soft meninges first. Metastatic lymphomas mostly cause symptoms throughout the nervous system and may include cranial hypertension, polyneuropathy, and multiple cranial neuropathies. It rarely involves the brain parenchyma and accounts for less than 1% of systemic lymphomas.
The origin of malignant lymphocytes in PCNSL remains unclear because of the lack of lymph nodes or lymphatic vessels in the CNS; T lymphocytes can enter the CNS, but B lymphocytes are rare, but most PCNSL are B lymphocytic tumors. It has been hypothesized that PCNSL tumor cells can originate anywhere in the body and migrate to the CNS. studies have shown differences in B-cell activation antigens between PCNSL and systemic lymphomas, suggesting that B-lymphocytes in lymphomas have a specific tropism for the CNS. lymphocytes in PCNSL are mainly concentrated in the perivascular space, i.e., between the vessel wall and the basement membrane and outer glial end-foot, and once the Once the basement membrane is breached, the lymphoma cells can enter the brain parenchyma.
2. Epidemiology
The annual incidence of PCNSL in the immunocompetent population is about 0.28/100,000; in AIDS patients, the annual incidence is significantly higher, at 4.7/100,000. The mean age of onset is 58 years in immunocompetent people and 43 years in AIDS patients. It is rare in children, and if it develops it is mostly accompanied by hereditary immunodeficiencies such as variant immunodeficiency disease, IgA deficiency, hyper-M-globulin syndrome, severe combined immunodeficiency, and Wiskott-Aldrich syndrome.
The most obvious risk factor for PCNSL is the presence of alterations in the patient’s immune system. The incidence of PCNSL is elevated in people with rheumatoid arthritis, systemic lupus erythematosus, nodular disease, and dry syndrome. AIDS is the most common immunodeficiency contributing to the development of PCNSL in patients with AIDS, which occurs in approximately 5% of patients and decreases with highly active antiretroviral therapy. In all immunodeficient patients, EBV accelerates the development of PCNSL. B lymphocytes can become latently infected after primary infection, and B cells infected with EBV can cause a certain subtype of B cells to never apoptosis, the latter growth being controlled by T lymphocytes. When T-lymphocyte regulation is lost due to immune system nonresponse, EBV-infected B cells grow indefinitely, eventually leading to monoclonal proliferation and tumor formation.
Previous reports have shown that PCNSL accounts for approximately 0.85-3.3% of all intracranial tumors. Data from the Central Brain Tumor Registry of the United States (CBTRUS) from 1990 and 1994 showed that the incidence of PCNSL increased to 4.1%. Associated factors include increased incidence of AIDS, improved diagnostic imaging techniques, vastly improved histological diagnostic techniques, and increased survival years in organ transplant patients on immunosuppressive drugs.
In a large sample of immunocompetent PCNSL cases, there were slightly more men, similar to the sex ratio in systemic lymphoma. Among AIDS patients, the sex ratio is significantly more in favor of males, due to the fact that the majority of HIV-infected patients in the U.S. There is no significant geographic or racial difference in the incidence of PCNSL.
3. Histology of the tumor
The lymphoma is soft in texture, varies in color, and has an indistinct interface with brain tissue when observed by the naked eye. The tumors grow as solid masses or sheets. The tumor is characterized by cells located around blood vessels, infiltration of paraneoplastic brain tissue and unclear borders. Rarely, tumor hemorrhage, cystic degeneration, necrosis, and endothelial hyperplasia are seen. Tumors may invade the walls of blood vessels and present with vasculitis-like manifestations.
Autopsy shows that the tumor has a significant occupying effect, invading or pushing out normal brain tissue. Localized absence of occupancy is rare, but extensive tissue infiltration is seen. The margins of invasive masses are often a mixture of tumor cells, reactive small lymphocytes, and reactive glial cells. Glial reactions containing atypical large astrocytes can sometimes be seen at the margins of lymphomas. If the biopsy is taken from the marginal area of the tumor, the diagnosis of astrocytoma is often made.
Microscopic examination of PCNSL shows characteristic vascular-centered growth of tumor cells and tumor infiltration of small arteries, microarteries, and small veins. microscopic pathological features of PCNSL include lymphatic manifestations of neoplastic cells, perivascular lymphatic infiltration, location of neoplastic cells within the vessel wall, and the presence of reticulostein. The new tumor cells within the vessel wall have a unique laminated structure, which is not present in other intracranial malignancies, and therefore has a differential diagnostic value. Multifarious reactive gliosis and reactive T-lymphocyte invasion are seen in the periphery of the tumor.
Histologically, most PCNSL tumors are typical of B-cell NHL. cells continuously express monotypic immunoglobulins, commonly IgM kappa and the B-cell-restricted antigen CD20. almost half are of the diffuse large-cell type according to the IWF (International Working Formulation) classification, the next The next are diffuse large cell-forming immune cell type, diffuse small cell dividing cell type, undifferentiated type and diffuse large and small cell type. Using the REAL (Revised European-American Lymphoma classification, TEAL) classification to simplify it, approximately 90% of PCNSL are included in diffuse B-cell lymphoma.
Regardless of whether the patient is immunocompetent or immunodeficient. Primary T-cell lymphoma accounts for 1% to 3% of PCNSL, and recently there has been a decrease in the age of onset in patients diagnosed and an increase in the number of reported cases occurring below the scenes. Because the disease is rare, its biological behavior and response to therapy remain unclear.
4. Clinical presentation
Similar to most brain diseases, patient symptoms are mostly determined by the site of the lesion and the occupying effect of the tumor. pcnsl mostly behaves similarly to cranial tumors, and the most common symptoms are headache, personality changes, and may present with increased intracranial pressure. Focal neurological deficits and seizure symptoms may also be present. The average time from symptom onset to definitive diagnosis is 2 to 3 months.
PCNSL often involves four sites: brain parenchyma (30 to 50%), soft meninges (10 to 25%), eye (10 to 25%) and spinal cord.
Tumors are most commonly located in the cerebral hemispheres, most often in the frontal lobes, and most often in the periventricular white matter, basal ganglia, and callosal limb. PCNSL is seen in the cerebellum and brainstem, and rarely in the spinal cord. 60%-70% of cases are solitary tumors. systemic dissemination is seen in about 7%-8% of advanced cases of PCNSL, most commonly with abdominal and retroperitoneal lymph node invasion. These metastases are most often found at autopsy, have little relationship to the disease process, and are generally not the cause of patient death.
There is an increasing trend of ocular involvement in PCNSL, either as a primary site or as a recurrent site. 10-25% of patients present with ocular symptoms, usually in the form of painless visual disturbances. Therefore, slit lamp microscopy should be performed in all patients diagnosed with PCNSL and in patients with recurrent disease.
5. Neuroimaging manifestations
The lesion is usually located in the deep brain, mostly in the paraventricular area, often solitary, and may also involve the eye, cerebrospinal fluid and spinal cord. The tumor is usually free of necrosis, hemorrhage, calcification and cystic changes, which is one of the differentiation points with other intracranial tumors. Despite the invasive nature of the tumor, peritumoral edema is not evident.
In patients with AIDS, the tumor is multifocal with variable imaging signal and ring-like enhancement on CT or MRI, which may be associated with central necrosis or hemorrhage.
PET and SPECT are also used as adjunctive imaging tools in the diagnosis of AIDS-associated PCNSL. CT or MRI do not distinguish toxoplasmosis from PCNSL, however, toxoplasmosis is hypometabolic on (FDG)-PET, whereas PCNSL is hypometabolic in image presentation. Thallium-201 SPECT also showed that PCNSL showed high uptake, while toxoplasmosis showed low uptake. Despite the high sensitivity and specificity of both tests, there are certain false positives and false negatives.
6.Diagnosis
Imaging examinations can diagnose intracranial tumors, and histopathological basis is required to establish the diagnosis of PCNSL. Specimens for pathological diagnosis are best obtained by stereotactic biopsy. For deep lesions, stereotactic biopsy is safe and effective. 15% of patients can have tumor cells detected by cerebrospinal fluid cytology. Most patients show non-specific cerebrospinal fluid abnormalities, such as increased cerebrospinal fluid protein in 75% of patients. Some patients who refuse tissue biopsy can be diagnosed definitively by cerebrospinal fluid examination. In addition to standard cytology, cerebrospinal fluid tumor markers, specific beta-2 microglobulin, immunophenotyping of cells, or clonal immunoglobulin gene alignments can help in the diagnosis.
In immunodeficient patients, PCR examination of EBV DNA in the cerebrospinal fluid is reliable and specific for the diagnosis of PCNSL. If EBV infection is determined to be present in the cerebrospinal fluid and PET shows hypermetabolism or thallium-SPECT shows high uptake, then PCNSL is 100% certain and a biopsy may not be performed at this time. In immunodeficient patients, biopsy of intracranial lesions can easily lead to CNS hemorrhage. Therefore, in patients with AIDS and other immunosuppressed conditions, the diagnosis can be reached by indirect means.
Diagnostically, CT examinations to determine disease stage, lumbar puncture, ophthalmic slit lamp examination and bone marrow aspiration are required to determine the extent of the disease and to rule out systemic lymphoma. Serologic HIV testing is necessary to rule out AIDS.
The use of corticosteroids prior to histologic examination may interfere with the correct diagnosis because corticosteroids may be directly cytotoxic to lymphocytes. The use of hormones may cause the tumor to become smaller or even disappear, while making the surgically obtained pathology specimen show normal or necrotic cells and no lymphoma cells can be found. Some scholars, however, consider the disappearance of tumors after hormone use as a specific pathological change in PCNSL. The use of hormones should be avoided until histological examination is performed. Although early MRI in these patients may show large tumors, the vast majority of patients have stable disease without hormone use prior to histologic examination. If hormone use is unavoidable and the histology obtained is inconclusive, the drug should be rapidly discontinued and promptly re-biopsied. At this time, close observation of changes in the disease is needed, because the tumor may grow rapidly after discontinuing hormones.
7.Treatment
(1) Surgical treatment
In patients with PCNSL, surgery is limited to stereotactic biopsy and decompression surgery in case of acute brain herniation caused by occupying effect. In patients not considered preoperatively for PCNSL, frozen sections can clarify the diagnosis, and if enough tissue has been obtained and a diagnosis of PCNSL can be confirmed, then the original surgical resection plan should be abandoned. Patients with occasional obstructive hydrocephalus should be promptly shunted. henry reported a median survival of 4.6 months with resection of the tumor alone. murray found a median patient survival of 1 month with resection of the tumor alone. The value of surgery for PCNSL patients is diagnostic, but not very helpful in treatment.
(2) Steroid hormones
Some lymphomas are very sensitive to steroid hormones. Lymphoma cells contain glucocorticoid receptors that induce apoptosis, leading to cell melting and tumor shrinkage within hours to days after hormone application. This effect is different from dexamethasone in reducing tumor-associated vasogenic edema. The reduction in tumor volume is temporary and recurs after a few months or soon after discontinuation of the drug. Dexamethasone is partially or completely effective in at least 60% of patients with PCNSL. If steroid hormones are discontinued prior to histologic biopsy, they should be used as soon as possible after obtaining tissue for examination to reduce neurologic symptoms.
(3) Radiotherapy
PCNSL is very sensitive to radiation therapy, and radiotherapy is the main treatment. Most tumors shrink or even disappear in a short period of time after radiotherapy. the survival of patients with PCNSL treated with radiotherapy after surgery ranges from 11.5 to 42 months, with a median survival time of only 17 months. The 5-year survival rate with radiation therapy alone is 7%.
In patients with PCNSL, radiation therapy must be whole-brain in scope, even if there is only a single lesion on neuroimaging and the tumor invasion spreads more extensively. The current recommendation is a whole-brain radiation dose of 40-50 Gy without booster. Patients who receive extensive (4 cm) radiation therapy have better disease control than those treated with standard radiation windows. The Karnofsky score and age correlate with the prognosis of radiation therapy, and patients with a Karnofsky score greater than 70 and age less than 60 have a better prognosis.
(4) Chemotherapy
Chemotherapy is the main treatment for PCNSL. Chemotherapy is effective for systemic NHLs, and the efficiency of high-dose methotrexate applied to brain metastases from systemic NHLs can reach 80%. Clinical data on large samples of PCNSL have shown that chemotherapy significantly improves the median survival of PCNSL up to 40 months, and the role of chemotherapy is increasingly appreciated.
It is now recognized that the efficacy of chemotherapy combined with radiotherapy is much better than that of radiotherapy alone, with a 5-year survival rate of 20-30%. For the regimen and timing of chemotherapy, there is a tendency to conclude that high-dose methotrexate chemotherapy should be applied before radiotherapy.
The use of systemic combination chemotherapy with cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP), which is effective for systemic NHLs, has yielded only short-term survival. Although CHOP regimens provide palliation, rapidly growing regrowth is often found at distant sites from the CNS primary lesion. Tumor recurrence after chemotherapy is not in the primary site but in the distant compartment, suggesting that the drug can only enter the tumor area where the blood-brain barrier is disrupted, while the tumor area with an intact blood-brain barrier is not sensitive to chemotherapy. Preliminary studies on the blood-brain barrier in PCNSL patients showed that the blood-brain barrier disrupted area was rapidly repaired about 5 weeks after the first chemotherapy. Therefore, to improve the effectiveness of chemotherapy, it is necessary to use drugs that can cross the blood-brain barrier and to use techniques that alter the permeability of the blood-brain barrier.
Methotrexate is currently recognized as the drug of choice for the early treatment of PCNSL. It inhibits dihydrofolate reductase, an essential coenzyme required for purine and thymine synthesis. High doses of methotrexate (>1g/m2) can cross the intact blood-brain barrier and the drug can reach tiny tumor lesions. This dose of methotrexate can also reach therapeutic concentrations in the cerebrospinal fluid. rapid IV dosing over 2-3 hours is more likely to achieve high concentrations in the cerebrospinal fluid than slow IV dosing over 24 hours, thus avoiding intrathecal administration. Thus, high doses of methotrexate can treat large, microscopic and soft meningeal tumors in the CNS. Gabbai et al. treated with 3 g/m2 of methotrexate and found that complete or partial treatment was achieved before radiotherapy with minimal toxic effects. abrey reported 52 patients treated with methotrexate (3.5 g/m2) supplemented with methylbenzylhydrazine and vincristine with a mean Survival time was 60 months.
The systemic toxic effects of methotrexate include bone marrow suppression, mucosal inflammation, and nephrotoxicity. Nephrotoxicity can be reduced by heavy water intake and urinary alkalinization. Folinic acid (formyltetrahydrofolate, a folate antagonist that blocks methotrexate) does not antagonize the toxic effects of methotrexate on malignant cells, but corrects the toxic effects on normal cells. Folic acid has a poor ability to penetrate the blood-brain barrier and significantly antagonizes the toxic effects of methotrexate on bone marrow and mucous membranes, while rarely affecting the efficacy of methotrexate in CNS lymphoma.
It is generally accepted that chemotherapy should be scheduled prior to radiation therapy. The advantages of doing so include: radiotherapy often causes rapid disappearance of lesions in a short period of time, making it difficult to judge the efficacy of subsequent chemotherapy; those who do not respond to chemotherapy can be identified at an early stage, and radiotherapy can be chosen for such patients, and no chemotherapy or adjustment of chemotherapy drugs can be made after the completion of radiotherapy; the risk of neurotoxic side effects can be reduced by using methotrexate before radiotherapy.
(5) Patients with immunosuppression
For patients with immune deficiency (e.g. AIDS), the efficacy depends on the progress of the patient’s systemic systems. Some patients can tolerate palliative radiotherapy, which can prolong survival for 5 months. Patients tend to die from systemic diseases such as opportunistic infections rather than PCNSL itself. High-dose methotrexate therapy is more effective in the few patients who can tolerate chemotherapy. Screening criteria for tolerating high-dose methotrexate therapy include a small viral load in the body; a CD4 T-cell count of ≥200/mm3; and the absence of opportunistic infections in all systemic systems. Recent reports have shown that immune reconstitution in AIDS patients can lead to regression of PCNSL. For AIDS patients with PCNSL, the routine application of ganciclovir, which can inhibit the growth of EBV, has certain efficacy.
(6) Recurrent PCNSL
The recurrence rate of PCNSL is about 40-60%. The treatment of recurrent PCNSL is very difficult. For most patients, remedial therapy can increase survival rates. Whole-brain radiotherapy can be applied to patients who did not previously receive radiotherapy. Some drugs that can be applied systemically and intrathecally are available for recurrence: methylbenzylhydrazine, lomustine, vincristine combination, sepiatide, high concentration of cytarabine, isocyclophosphamide, carboplatin, etoposide. Intrathecal therapy via the Ommaya reservoir capsule is effective in patients with soft meningeal tumors; this therapy allows for more uniform drug distribution than intrathecal therapy via lumbar puncture.
Temozolomide is an alkylated cytotoxic substance that readily penetrates the normal blood-brain barrier and is used to treat malignant glioblastomas. In cases of renal insufficiency or systemic conditions that do not tolerate methotrexate, temozolomide is used to obtain better results in the treatment of PCNSL. The better tolerability and relatively low nephrotoxicity of temozolomide make it a potential alternative to methotrexate regimens in some patients or in patients with recurrence. However, more clinical data are needed to further confirm this.
There have been studies of high-dose chemotherapy combined with autologous stem cell transplantation for relapsed PCNSL, and Soussain et al. used high-dose leucovorin and triamcinolone acetonide chemotherapy combined with autologous stem cell transplantation to treat patients with relapsed PCNSL, resulting in an extended median survival of 3 years. This may be a better option for patients in better general condition.